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Wang J, Xie Y, Zhu G, Qian Y, Sun Q, Li H, Li C. Acidity-unlocked glucose oxidase as drug vector to boost intratumor copper homeostatic imbalance-enhanced cuproptosis for metastasis inhibition and anti-tumor immunity. Biomaterials 2025; 319:123207. [PMID: 40037207 DOI: 10.1016/j.biomaterials.2025.123207] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2024] [Revised: 01/20/2025] [Accepted: 02/23/2025] [Indexed: 03/06/2025]
Abstract
As one of the key tools of biocatalysis, natural enzymes have received extensive attention due to their unique activity. However, the non-selective catalysis and early leakage induced by delivery dependency of natural enzymes can cause side effects on normal tissues. Moreover, although cuproptosis is an emerging tumor-inhibiting programmed cell death, the occurrence of cuproptosis leads to high expression of Cu-dependent lysyl oxidase-like 2 (LOXL2), which promotes tumor metastasis. Herein, in order to intelligently regulate the "OFF-to-ON" catalytic activity of glucose oxidase (a natural enzyme called GOx) and simultaneously inhibit tumor metastasis caused by Cu imbalance, an acidity-unlocked GOx system drug carrier was constructed by co-assembling Cu ions and omeprazole (OPZ) on GOx exposing sulfhydryl and hydrophobic pockets. The GOx activity is significantly inhibited due to the coordination of Cu ions with sulfhydryl groups and the interaction of hydrophobic small molecule OPZ with hydrophobic bags, which results in specificity for tumor cells and ensures the safety of GOx in blood circulation. Meanwhile, dysregulation of intracellular Cu homeostasis that impairs the Cu-dependence of LOXL2 not only inhibits critical signaling during epithelial-mesenchymal transformation (EMT) and extracellular matrix (ECM) remodelling to prevent tumor metastasis, but also exacerbates enhanced cuproptosis induced by tumor metabolic stress, thereby reversing the immunosuppressive microenvironment. This strategy of acidity-unlocked the catalytic function of natural enzymes and LOXL2 activity inhibition provides a novel option for enhancing cuproptosis to inhibit tumor metastasis and anti-tumor immunity.
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Affiliation(s)
- Junrong Wang
- Institute of Frontier Chemistry, School of Chemistry and Chemical Engineering, Shandong University, Qingdao, Shandong, 266237, PR China
| | - Yulin Xie
- Institute of Frontier Chemistry, School of Chemistry and Chemical Engineering, Shandong University, Qingdao, Shandong, 266237, PR China
| | - Guoqing Zhu
- Institute of Frontier Chemistry, School of Chemistry and Chemical Engineering, Shandong University, Qingdao, Shandong, 266237, PR China
| | - Yanrong Qian
- Institute of Frontier Chemistry, School of Chemistry and Chemical Engineering, Shandong University, Qingdao, Shandong, 266237, PR China
| | - Qianqian Sun
- Institute of Frontier Chemistry, School of Chemistry and Chemical Engineering, Shandong University, Qingdao, Shandong, 266237, PR China.
| | - Haoze Li
- Institute of Frontier Chemistry, School of Chemistry and Chemical Engineering, Shandong University, Qingdao, Shandong, 266237, PR China
| | - Chunxia Li
- Institute of Frontier Chemistry, School of Chemistry and Chemical Engineering, Shandong University, Qingdao, Shandong, 266237, PR China.
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Ton Nu QC, Deka G, Park PH. CD8 + T cell-based immunotherapy: Promising frontier in human diseases. Biochem Pharmacol 2025; 237:116909. [PMID: 40179991 DOI: 10.1016/j.bcp.2025.116909] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2024] [Revised: 02/28/2025] [Accepted: 03/26/2025] [Indexed: 04/05/2025]
Abstract
The abundant cell components of the adaptive immune system called T lymphocytes (T cells) play important roles in mediating immune responses to eliminate the invaders and create the memory of the germs to form a new immunity for the next encounter. Among them, cytotoxic T cells expressing cell-surface CD8 are the most critical effector cells that directly eradicate the target infected cells by recognizing antigens presented by major histocompatibility complex class I molecules to protect our body from pathological threats. In the continuous evolution of immunotherapy, various CD8+ T cell-based therapeutic strategies have been developed based on the role and molecular concept of CD8+ T cells. The emergence of such remarkable therapies provides promising hope for multiple human disease treatments such as autoimmunity, infectious disease, cancer, and other non-infectious diseases. In this review, we aim to discuss the current knowledge on the utilization of CD8+ T cell-based immunotherapy for the treatment of various diseases, the molecular basis involved, and its limitations. Additionally, we summarize the recent advances in the use of CD8+ T cell-based immunotherapy and provide a comprehensive overview of CD8+ T cells, including their structure, underlying mechanism of function, and markers associated with CD8+ T cell exhaustion. Building upon these foundations, we delineate the advancement of CD8+ T cell-based immunotherapies with fundamental operating principles followed by research studies, and challenges, as well as illustrate human diseases involved in this development.
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Affiliation(s)
- Quynh Chau Ton Nu
- College of Pharmacy, Yeungnam University, Gyeongsan, Republic of Korea
| | - Gitima Deka
- College of Pharmacy, Yeungnam University, Gyeongsan, Republic of Korea
| | - Pil-Hoon Park
- College of Pharmacy, Yeungnam University, Gyeongsan, Republic of Korea; Research institute of cell culture, Yeungnam University, Gyeongsan, Republic of Korea.
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3
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Sultan MH, Zhan Q, Wang Y, Xia Y, Jia X. Precision oncolytic viral therapy in colorectal cancer: Genetic targeting and immune modulation for personalized treatment (Review). Int J Mol Med 2025; 56:104. [PMID: 40342021 PMCID: PMC12081034 DOI: 10.3892/ijmm.2025.5545] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2024] [Accepted: 04/09/2025] [Indexed: 05/11/2025] Open
Abstract
Colorectal cancer (CRC) is a leading health issue and treatments to eradicate it, such as conventional chemotherapy, are non‑selective and come with a number of complications. The present review focuses on the relatively new area of precision oncolytic viral therapy (OVT), with genetic targeting and immune modifications that offer a new future for CRC treatment. In the present review, an overview of the selection factors that are considered optimal for an oncolytic virus, mechanisms of oncolysis and immunomodulation applied to the OVT, as well as new strategies to improve the efficacy of this method are described. Additionally, cause‑and‑effect relationships are examined for OVT efficacy, mediated by the tumor microenvironment, and directions for genetic manipulation of viral specificity are explored. The possibility of synergy between OVT and immune checkpoint inhibitors and other treatment approaches are demonstrated. Incorporating the details of the present review, biomarker‑guided combination therapies in precision OVT for individualized CRC care, significant issues and future trends in this required area of medicine are highlighted. Increasingly, OVT is leaving the experimental stage and may become routine practice; it provides a new perspective on overcoming CRC and highlights the importance of further research and clinical work.
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Affiliation(s)
- Muhammad Haris Sultan
- College of Life Sciences and Medicine, Xinyuan Institute of Medicine and Biotechnology, Zhejiang Sci-Tech University, Hangzhou, Zhejiang 310018, P.R. China
- Center for Translational Medicine and Precision Medicine, Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, Zhejiang 325000, P.R. China
| | - Qi Zhan
- College of Life Sciences and Medicine, Xinyuan Institute of Medicine and Biotechnology, Zhejiang Sci-Tech University, Hangzhou, Zhejiang 310018, P.R. China
| | - Yigang Wang
- College of Life Sciences and Medicine, Xinyuan Institute of Medicine and Biotechnology, Zhejiang Sci-Tech University, Hangzhou, Zhejiang 310018, P.R. China
| | - Yulong Xia
- Center for Translational Medicine and Precision Medicine, Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, Zhejiang 325000, P.R. China
| | - Xiaoyuan Jia
- College of Life Sciences and Medicine, Xinyuan Institute of Medicine and Biotechnology, Zhejiang Sci-Tech University, Hangzhou, Zhejiang 310018, P.R. China
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Qian H, Ali H, Karri V, Low JT, Ashley DM, Heimberger AB, Godley LA, Sonabend AM, Dmello C. Beyond DNA damage response: Immunomodulatory attributes of CHEK2 in solid tumors. Oncotarget 2025; 16:445-453. [PMID: 40492861 DOI: 10.18632/oncotarget.28740] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/12/2025] Open
Abstract
The CHEK2 gene serves a canonical role in the DNA damage response (DDR) pathway encoding the regulatory kinase CHK2 in the homologous recombination (HR) repair of double-strand breaks (DSB). Although CHEK2 is traditionally considered a tumor suppressor gene, recent studies suggest additional functions. Across several cohort studies, CHEK2 expression was negatively correlated with the efficacy of immune checkpoint inhibitors (ICI), which target the interaction between effector immune and tumor cells. This review explores two possible explanations for this observed phenomenon: the first relating to the canonical role of CHEK2, and the second introducing a novel role of the CHEK2 gene in immunomodulation of the tumor microenvironment (TME). DDR mutations have been implicated in increased levels of tumor mutation burden (TMB), often manifesting as neoepitope expression on the tumor cell surface recognized by effector immune cells. As a result, impaired DNA repair due to CHEK2 loss of function, either from germline deleterious variants or acquired mutations, results in the recruitment of CD8+ cytotoxic T-cells and subsequent efficacy of ICI treatment. However, functional loss of CHEK2 may be directly involved in potentiating the immune response through canonical inflammatory and anti-tumor pathways, acting through the cGAS-STING pathway. Although the exact mechanism by which CHEK2 modulates immune responses is still under investigation, combination therapy with CHEK1/2 inhibition and ICI immunotherapy has shown benefit in preclinical studies of several solid tumors.
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Affiliation(s)
- Helen Qian
- Department of Neurological Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
- Northwestern Medicine Malnati Brain Tumor Institute of the Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
- College of Arts and Sciences, Cornell University, Ithaca, NY 14850, USA
| | - Heba Ali
- Department of Neurological Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
- Northwestern Medicine Malnati Brain Tumor Institute of the Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
- Department of Zoology, Faculty of Science, Assiut University, Assiut, Egypt
| | - Vivekanudeep Karri
- Department of Neurological Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
- Northwestern Medicine Malnati Brain Tumor Institute of the Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
| | - Justin T Low
- Duke University School of Medicine, Duke University, Durham, NC 27708, USA
| | - David M Ashley
- Duke University School of Medicine, Duke University, Durham, NC 27708, USA
| | - Amy B Heimberger
- Department of Neurological Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
- Northwestern Medicine Malnati Brain Tumor Institute of the Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
| | - Lucy A Godley
- Division of Hematology/Oncology, Department of Medicine, Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL 60611, USA
| | - Adam M Sonabend
- Department of Neurological Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
- Northwestern Medicine Malnati Brain Tumor Institute of the Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
| | - Crismita Dmello
- Department of Neurological Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
- Northwestern Medicine Malnati Brain Tumor Institute of the Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
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5
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Zhou Q, Jiang Z, Ye T, Yu L, Wang Q, Lin P, Shao Y. Prognostic value of platelet-to-lymphocyte ratio in hepatocellular carcinoma patients treated with immune checkpoint inhibitors: a systematic review and meta-analysis. BMC Gastroenterol 2025; 25:437. [PMID: 40481391 PMCID: PMC12144809 DOI: 10.1186/s12876-025-04028-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2024] [Accepted: 05/23/2025] [Indexed: 06/11/2025] Open
Abstract
BACKGROUND The prognostic significance of the Platelet-to-Lymphocyte Ratio (PLR) in patients with hepatocellular carcinoma (HCC) undergoing treatment with immune checkpoint inhibitors (ICIs) remains uncertain. A systematic review and meta-analysis was conducted to assess the prognostic value of PLR in HCC patients receiving ICIs. METHODS Potential eligible studies that explored the role of pretreatment PLR in HCC patients received ICIs treatment were retrieved using PubMed, Embase, and the Cochrane Library databases up to March 31, 2024. The Newcastle-Ottawa Scale was used to assess the study quality. Pooled hazard ratios (HRs) and 95% confidence intervals (CIs) were utilized to investigate the correlation between PLR and both overall survival (OS) and progression-free survival (PFS). Subgroup analysis along with assessments for publication bias and sensitivity were performed to identify any sources of heterogeneity and to confirm the reliability of the pooled outcomes. RESULTS A total of 15 studies were analyzed, with the aggregate findings showing that elevated PLR levels were associated with poorer OS (HR: 1.79, 95%CI: 1.44-2.22, P < 0.001) and PFS (HR: 1.80, 95%CI: 1.40-2.30, P < 0.001) in HCC patients treated with ICIs. Moreover, the subgroup analyses did not alter the direction of results for OS and PFS. Publication bias and sensitivity analysis revealed that there was no significant publication bias among the articles and the pooled results were robust. CONCLUSION These results show that elevated PLR is related to worse survival in patients with HCC treated with ICIs. PLR may therefore represent an effective indicator of prognosis in HCC undergoing ICIs treatment. TRIAL REGISTRATION This study is registered with the International Platform of Registered Systematic Review and Meta-analysis Protocols (INPLASY202450079).
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Affiliation(s)
- Qingtian Zhou
- Department of Gastroenterology, The Third Affiliated People's Hospital of Fujian University of Traditional Chinese Medicinee, No. 363, Guobin Avenue, Fuzhou City, Fujian Province, China
| | - Zewen Jiang
- Department of Infectious Diseases, The 900 Hospital of the Joint Logistics Team of the Chinese PLA, Fuzhou, Fujian, China
| | - Tingting Ye
- Department of Gastroenterology, The Third Affiliated People's Hospital of Fujian University of Traditional Chinese Medicinee, No. 363, Guobin Avenue, Fuzhou City, Fujian Province, China
| | - Li Yu
- Department of Gastroenterology, The Third Affiliated People's Hospital of Fujian University of Traditional Chinese Medicinee, No. 363, Guobin Avenue, Fuzhou City, Fujian Province, China
| | - Qinglian Wang
- Department of Gastroenterology, The Third Affiliated People's Hospital of Fujian University of Traditional Chinese Medicinee, No. 363, Guobin Avenue, Fuzhou City, Fujian Province, China
| | - Pin Lin
- Department of Gastroenterology, The Third Affiliated People's Hospital of Fujian University of Traditional Chinese Medicinee, No. 363, Guobin Avenue, Fuzhou City, Fujian Province, China
| | - Yanfeng Shao
- Department of Gastroenterology, The Third Affiliated People's Hospital of Fujian University of Traditional Chinese Medicinee, No. 363, Guobin Avenue, Fuzhou City, Fujian Province, China.
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6
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Feng H, Jin Y, Wu B. Strategies for neoantigen screening and immunogenicity validation in cancer immunotherapy (Review). Int J Oncol 2025; 66:43. [PMID: 40342048 PMCID: PMC12101193 DOI: 10.3892/ijo.2025.5749] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2025] [Accepted: 04/11/2025] [Indexed: 05/11/2025] Open
Abstract
Cancer immunotherapy stimulates and enhances antitumor immune responses to eliminate cancer cells. Neoantigens, which originate from specific mutations within tumor cells, are key targets in cancer immunotherapy. Neoantigens manifest as abnormal peptide fragments or protein segments that are uniquely expressed in tumor cells, making them highly immunogenic. As a result, they activate the immune system, particularly T cell‑mediated immune responses, effectively identifying and eliminating tumor cells. Certain tumor‑associated antigens that are abnormally expressed in normal host proteins in cancer cells are promising targets for immunotherapy. Neoantigens derived from mutated proteins in cancer cells offer true cancer specificity and are often highly immunogenic. Furthermore, most neoantigens are unique to each patient, highlighting the need for personalized treatment strategies. The precise identification and screening of neoantigens are key for improving treatment efficacy and developing individualized therapeutic plans. The neoantigen prediction process involves somatic mutation identification, human leukocyte antigen (HLA) typing, peptide processing and peptide‑HLA binding prediction. The present review summarizes the major current methods used for neoantigen screening, available computational tools and the advantages and limitations of various techniques. Additionally, the present review aimed to summarize experimental strategies for validating the immunogenicity of the predicted neoantigens, which will determine whether these neoantigens can effectively trigger immune responses, as well as challenges encountered during neoantigen screening, providing relevant recommendations for the optimization of neoantigen‑based immunotherapy.
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Affiliation(s)
- Hua Feng
- College of Life Sciences, China Jiliang University, Hangzhou, Zhejiang 310018, P.R. China
| | - Yuanting Jin
- College of Life Sciences, China Jiliang University, Hangzhou, Zhejiang 310018, P.R. China
| | - Bin Wu
- Department of Neurosurgery, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine, Chinese Academy of Sciences, Hangzhou, Zhejiang 310022, P.R. China
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Xu G, Jiang Y, Tu Z, Li Y, Xu X, Tong R, Jiang N, Xie K, Chen D, Wu J. Diverse RNA methylation patterns in neutrophils: key drivers in hepatocellular carcinoma. Clin Transl Oncol 2025; 27:2527-2543. [PMID: 39621240 DOI: 10.1007/s12094-024-03756-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2024] [Accepted: 10/04/2024] [Indexed: 05/17/2025]
Abstract
BACKGROUND Neutrophils, crucial in the immune system, have recently been implicated in promoting malignancy. RNA methylation, an essential epigenetic feature, plays a key role in tumor microenvironment (TME) reprogramming. However, the relationship between neutrophils and RNA methylation in hepatocellular carcinoma (HCC) remains unclear. METHODS We analyzed single-cell sequencing data from HCC, focusing on cell subtype and TME construction. RNA methylation "writers" were selected, and their expression in neutrophils was evaluated. Two neutrophil subtypes (high/low RNA methylation) were identified. Differentially expressed genes (DEGs) between these subtypes were confirmed, leading to the identification of 6 molecular subtypes via consensus clustering. A prognostic scoring system was developed using LASSO Cox regression, resulting in a novel neutrophil RNA methylation (NRM) scoring system to assess TME heterogeneity and clinical features. RESULTS TRPM3, specifically expressed in HCC-infiltrating neutrophils, may regulate RNA modification in tumor pathogenesis. HCC patients were stratified into low/high-NRM score groups, further refined into an advanced NRM (a-NRM) score by incorporating lncRNA data. High a-NRM scores correlated with advanced TNM stage, higher pathological grade, and increased suppressive immune cells. A nomogram incorporating the a-NRM score demonstrated a concordance index indicative of good predictive performance. CONCLUSIONS The a-NRM score is a reliable predictor of prognosis and could guide treatment selection in HCC patients, enhancing clinical response to immunotherapy. TRPM3 also presents as a potential therapeutic target in HCC.
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Affiliation(s)
- Guangming Xu
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
| | - Yifan Jiang
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
| | - Zhenhua Tu
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
| | - Yu Li
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
| | - Xiaofeng Xu
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
| | - Rongliang Tong
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
| | - Nan Jiang
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
| | - Kai Xie
- Department of Anesthesiology, Shaoxing People's Hospital, Zhejiang University, Shaoxing, 312000, China
| | - Diyu Chen
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China.
| | - Jian Wu
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China.
- NHC Key Laboratory of Combined Multi-Organ Transplantation, Key Laboratory of Organ Transplantation, Hangzhou, Zhejiang Province, China.
- Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment for Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences(2019RU019), Hangzhou, China.
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Hangzhou, China.
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8
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Ma L, Mao JH, Barcellos-Hoff MH. Systemic inflammation in response to radiation drives the genesis of an immunosuppressed tumor microenvironment. Neoplasia 2025; 64:101164. [PMID: 40184664 PMCID: PMC11999686 DOI: 10.1016/j.neo.2025.101164] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2024] [Revised: 03/24/2025] [Accepted: 03/27/2025] [Indexed: 04/07/2025]
Abstract
The composition of the tumor immune microenvironment has become a major determinant of response to therapy, particularly immunotherapy. Clinically, a tumor microenvironment lacking lymphocytes, so-called "cold" tumors, are considered poor candidates for immune checkpoint inhibition. In this review, we describe the diversity of the tumor immune microenvironment in breast cancer and how radiation exposure alters carcinogenesis. We review the development and use of a radiation-genetic mammary chimera model to clarify the mechanism by which radiation acts. Using the chimera model, we demonstrate that systemic inflammation elicited by a low dose of radiation is key to the construction of an immunosuppressive tumor microenvironment, resulting in aggressive, rapidly growing tumors lacking lymphocytes. Our experimental studies inform the non-mutagenic mechanisms by which radiation affects cancer and provide insight into the genesis of cold tumors.
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Affiliation(s)
- Lin Ma
- Department of Stomatology, Shenzhen University General Hospital, Shenzhen University, Shenzhen, 518055, China
| | - Jian-Hua Mao
- Biological Systems and Engineering Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA
| | - Mary Helen Barcellos-Hoff
- Department of Radiation Oncology, School of Medicine, Helen Diller Comprehensive Cancer Center, University of California, San Francisco, CA 94143 USA.
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9
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Fang B, Lu Y, Li X, Wei Y, Ye D, Wei G, Zhu Y. Targeting the tumor microenvironment, a new therapeutic approach for prostate cancer. Prostate Cancer Prostatic Dis 2025; 28:260-269. [PMID: 38565910 DOI: 10.1038/s41391-024-00825-z] [Citation(s) in RCA: 10] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2023] [Revised: 03/17/2024] [Accepted: 03/21/2024] [Indexed: 04/04/2024]
Abstract
BACKGROUND A growing number of studies have shown that in addition to adaptive immune cells such as CD8 + T cells and CD4 + T cells, various other cellular components within prostate cancer (PCa) tumor microenvironment (TME), mainly tumor-associated macrophages (TAMs), cancer-associated fibroblasts (CAFs) and myeloid-derived suppressor cells (MDSCs), have been increasingly recognized as important modulators of tumor progression and promising therapeutic targets. OBJECTIVE In this review, we aim to delineate the mechanisms by which TAMs, CAFs and MDSCs interact with PCa cells in the TME, summarize the therapeutic advancements targeting these cells and discuss potential new therapeutic avenues. METHODS We searched PubMed for relevant studies published through December 10 2023 on TAMs, CAFs and MDSCs in PCa. RESULTS TAMs, CAFs and MDSCs play a critical role in the tumorigenesis, progression, and metastasis of PCa. Moreover, they substantially mediate therapeutic resistance against conventional treatments including anti-androgen therapy, chemotherapy, and immunotherapy. Therapeutic interventions targeting these cellular components have demonstrated promising effects in preclinical models and several clinical trials for PCa, when administrated alone, or combined with other anti-cancer therapies. However, the lack of reliable biomarkers for patient selection and incomplete understanding of the mechanisms underlying the interactions between these cellular components and PCa cells hinder their clinical translation and utility. CONCLUSION New therapeutic strategies targeting TAMs, CAFs, and MDSCs in PCa hold promising prospects. Future research endeavors should focus on a more comprehensive exploration of the specific mechanisms by which these cells contribute to PCa, aiming to identify additional drug targets and conduct more clinical trials to validate the safety and efficacy of these treatment strategies.
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Affiliation(s)
- Bangwei Fang
- Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Genitourinary Cancer Institute, Shanghai, 200032, China
| | - Ying Lu
- Key Laboratory of Metabolism and Molecular Medicine of the Ministry of Education, Department of Biochemistry and Molecular Biology of School of Basic Medical Sciences, Shanghai Medical College of Fudan University, Shanghai, China
| | - Xiaomeng Li
- Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Genitourinary Cancer Institute, Shanghai, 200032, China
| | - Yu Wei
- Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Genitourinary Cancer Institute, Shanghai, 200032, China
| | - Dingwei Ye
- Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Genitourinary Cancer Institute, Shanghai, 200032, China
| | - Gonghong Wei
- Key Laboratory of Metabolism and Molecular Medicine of the Ministry of Education, Department of Biochemistry and Molecular Biology of School of Basic Medical Sciences, Shanghai Medical College of Fudan University, Shanghai, China
| | - Yao Zhu
- Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
- Shanghai Genitourinary Cancer Institute, Shanghai, 200032, China.
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10
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Alim L, Adityan S, Chen R, Neilson T, Coleborn E, Wilkinson AN, He Y, Irgam G, Bhavsar C, Lourie R, Rogers R, Cabraal N, Jagasia N, Chetty N, Perrin L, Hooper JD, Steptoe R, Wu SY. Antigen presentation potential is variable among human ovarian tumour and syngeneic murine models and dictates pre-clinical outcomes of immunotherapy. Biomed Pharmacother 2025; 187:118141. [PMID: 40347847 DOI: 10.1016/j.biopha.2025.118141] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2024] [Revised: 04/24/2025] [Accepted: 05/05/2025] [Indexed: 05/14/2025] Open
Abstract
High grade serous ovarian carcinoma (HGSC) is a fatal gynaecological malignancy with limited therapeutic options. Immunotherapies targeting MHC-I-dependent antigen presentation offer potential. Currently, the antigen presentation machinery (APM) of widely used syngeneic murine HGSC models remains poorly characterised, limiting translational relevance. Here, we systematically evaluate APM gene expression in syngeneic murine and patient samples. Tap1 and Psmb8 were identified as critical APM markers, deficient in murine models and strongly correlating with MHC-I expression. Hierarchical clustering correlation analysis using these markers revealed that ID8-p53⁻/⁻BRCA1⁻/⁻ was the most strongly correlated model and aligned with the largest patient subset. Moreover, ID8-ip1 correlated to the smaller second patient subset strongly. The low MHC-I expressing IG10 model was unique clustering alongside patient derived LP28 tumour and not fitting either patient subset. In vivo test of a novel combination immune therapy consisting of Flt3L, Poly(I:C), and paclitaxel therapy demonstrated significantly reduced tumour burden in high APM models (p53⁻/⁻BRCA1⁻/⁻, ID8-ip1; p < 0.01), but not IG10. Furthermore, high expressing MHC-I models were linked to enhanced DC expansion, CD8⁺ T-cell infiltration, and effector differentiation (131 % increase in ID8-ip1), alongside improved CD8⁺ T-cell activation and CD86⁺ B-cell co-stimulation. These findings establish MHC-I as a predictive biomarker for immunotherapy response and underscore the need for APM-enhancing strategies in antigen-poor tumours. By bridging murine models to human APM heterogeneity, this work provides a framework for optimising preclinical immunotherapy evaluation and patient stratification, advancing tailored therapeutic approaches for HGSC.
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Affiliation(s)
- Louisa Alim
- School of Biomedical Sciences, The University of Queensland, Brisbane, Queensland 4072, Australia
| | - Siddharth Adityan
- School of Biomedical Sciences, The University of Queensland, Brisbane, Queensland 4072, Australia
| | - Rui Chen
- School of Biomedical Sciences, The University of Queensland, Brisbane, Queensland 4072, Australia
| | - Trent Neilson
- School of Biomedical Sciences, The University of Queensland, Brisbane, Queensland 4072, Australia
| | - Elaina Coleborn
- School of Biomedical Sciences, The University of Queensland, Brisbane, Queensland 4072, Australia
| | - Andrew N Wilkinson
- School of Biomedical Sciences, The University of Queensland, Brisbane, Queensland 4072, Australia
| | - Yaowu He
- Mater Research Institute - The University of Queensland, Translational Research Institute, Woolloongabba, Queensland 4102, Australia
| | - Gowri Irgam
- School of Biomedical Sciences, The University of Queensland, Brisbane, Queensland 4072, Australia
| | - Chintan Bhavsar
- School of Biomedical Sciences, The University of Queensland, Brisbane, Queensland 4072, Australia
| | - Rohan Lourie
- Mater Ovarian Cancer Research Collaborative, Mater Adult Hospital, South Brisbane, Queensland 4101, Australia; Mater Health Services, South Brisbane, Queensland 4101, Australia
| | - Rebecca Rogers
- Mater Ovarian Cancer Research Collaborative, Mater Adult Hospital, South Brisbane, Queensland 4101, Australia; Mater Health Services, South Brisbane, Queensland 4101, Australia
| | - Nimithri Cabraal
- Mater Ovarian Cancer Research Collaborative, Mater Adult Hospital, South Brisbane, Queensland 4101, Australia; Mater Health Services, South Brisbane, Queensland 4101, Australia
| | - Nisha Jagasia
- Mater Ovarian Cancer Research Collaborative, Mater Adult Hospital, South Brisbane, Queensland 4101, Australia; Mater Health Services, South Brisbane, Queensland 4101, Australia
| | - Naven Chetty
- Mater Ovarian Cancer Research Collaborative, Mater Adult Hospital, South Brisbane, Queensland 4101, Australia; Mater Health Services, South Brisbane, Queensland 4101, Australia
| | - Lewis Perrin
- Mater Ovarian Cancer Research Collaborative, Mater Adult Hospital, South Brisbane, Queensland 4101, Australia; Mater Health Services, South Brisbane, Queensland 4101, Australia
| | - John D Hooper
- Mater Research Institute - The University of Queensland, Translational Research Institute, Woolloongabba, Queensland 4102, Australia; Mater Ovarian Cancer Research Collaborative, Mater Adult Hospital, South Brisbane, Queensland 4101, Australia
| | - Raymond Steptoe
- Frazer Institute, University of Queensland, Brisbane, Australia
| | - Sherry Y Wu
- School of Biomedical Sciences, The University of Queensland, Brisbane, Queensland 4072, Australia.
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11
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Li L, Wang B, Li Q, Zhang L, Li C, Jin A, Qi H, Tang Y. A TCR nanovesicle antibody for redirecting T cells and reversing immunosuppression as a tumor immunotherapy strategy. J Control Release 2025; 384:113869. [PMID: 40412660 DOI: 10.1016/j.jconrel.2025.113869] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2025] [Revised: 05/07/2025] [Accepted: 05/19/2025] [Indexed: 05/27/2025]
Abstract
T-cell receptor T-cell engagers (TCR-TCE) are soluble bispecific proteins composed of TCR and anti-CD3 antibodies, which can effectively redirect tumor-infiltrating T cells to kill tumor cells. However, TCR-TCE development and clinical application are significantly hindered by the instability of natural TCRs and immunosuppressive tumor microenvironment, underscoring the urgent need for alternative engineering strategies. Here, we describe a strategy that utilizes artificial cell membrane nanoparticle technology to generate a TCR nanovesicle antibody (TPC NV), which presents tumor-specific TCR, anti-CD3, and PD-1 antibodies on its membrane, representing a novel TCR-TCE with therapeutic efficacy against solid tumors. TPC NV binds to tumor cells through TCR, redirects tumor-infiltrating T cells via anti-CD3 antibodies, and reverses immunosuppression with anti-PD-1 antibodies, thereby inducing a broad-spectrum T cell response that effectively eliminates established tumors. Furthermore, epacadostat, an inhibitor of indoleamine 2,3-dioxygenase, can be loaded into TPC NV to suppress regulatory T cell (Treg) generation and enhance dendritic cell (DC) maturation by inhibiting tumor tryptophan metabolism. This dual action amplifies adaptive immune activation and triggers a robust systemic anti-tumor immune response.
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Affiliation(s)
- Luo Li
- Department of Laboratory Medicine, Women and Children's Hospital of Chongqing Medical University, Chongqing 401147, PR China; Department of Laboratory Medicine, Chongqing Health Center for Women and Children, Chongqing 401147, PR China.
| | - Bozhi Wang
- Chongqing Key Laboratory of Basic and Translational Research of Tumor Immunology, Chongqing Medical University, Chongqing 400016, PR China; Department of Immunology, College of Basic Medicine, Chongqing Medical University, Chongqing 400016, PR China
| | - Qian Li
- Department of Laboratory Medicine, Women and Children's Hospital of Chongqing Medical University, Chongqing 401147, PR China; Department of Laboratory Medicine, Chongqing Health Center for Women and Children, Chongqing 401147, PR China
| | - Liang Zhang
- Department of Ultrasound the First Affiliated Hospital of Chongqing Medical University, Chongqing 400010, PR China
| | - Chunli Li
- Department of Laboratory Medicine, Women and Children's Hospital of Chongqing Medical University, Chongqing 401147, PR China; Department of Laboratory Medicine, Chongqing Health Center for Women and Children, Chongqing 401147, PR China.
| | - Aishun Jin
- Chongqing Key Laboratory of Basic and Translational Research of Tumor Immunology, Chongqing Medical University, Chongqing 400016, PR China; Department of Immunology, College of Basic Medicine, Chongqing Medical University, Chongqing 400016, PR China.
| | - Hongbo Qi
- Department of Obstetrics and Gynecology, Women and Children's Hospital of Chongqing Medical University, Chongqing 401147, PR China; Chongqing Key Laboratory of Maternal and Fetal Medicine, Chongqing Medical University, Chongqing 400016, PR China.
| | - Yu Tang
- Department of Ultrasound the First Affiliated Hospital of Chongqing Medical University, Chongqing 400010, PR China.
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12
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Lee KW, Zang DY, Kim HD, Kim JW, Kim BJ, Kang YK, Ryu MH, Kim HK. Multicenter phase Ib/II study of second-line durvalumab and tremelimumab in combination with paclitaxel in patients with biomarker-selected metastatic gastric cancer. Br J Cancer 2025:10.1038/s41416-025-03052-y. [PMID: 40399487 DOI: 10.1038/s41416-025-03052-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2024] [Revised: 04/24/2025] [Accepted: 05/01/2025] [Indexed: 05/23/2025] Open
Abstract
BACKGROUND This multicenter phase Ib/II trial aimed to evaluate the safety and efficacy of combining durvalumab, tremelimumab, and paclitaxel as second-line treatment for biomarker-selected patients with metastatic gastric cancer. METHODS In phase Ib, the standard 3 + 3 dose escalation method was used. Durvalumab and tremelimumab were administered every 4 weeks for 13 and 4 cycles, respectively, combining paclitaxel 80 mg/m2 (dose level 2) or 60 mg/m2 (dose level 1) on days 1, 8, and 15. The primary outcome for phase II was the objective response rate (ORR). RESULTS In phase Ib (n = 7), dose level-1 was selected as the recommended phase II dose. In phase II, 48 patients were enrolled: microsatellite instability-high or deficient mismatch repair protein tumors (n = 16); EBV-positive tumors (n = 15); high tumor mutation burden ( ≥ 5/Mb) (n = 11); CD274 amplification (n = 5); and POLD1 mutation (n = 1). The ORR was 52.1%, meeting the primary endpoint. The median progression-free survival and overall survival were 5.3 and 13.1 months, respectively. The most common any-grade and grade 3-4 adverse events were anemia (41.7%) and neutropenia (10.4%), respectively. CONCLUSIONS Durvalumab-tremelimumab with paclitaxel was tolerable and efficacious in biomarker-selected gastric cancer patients as a second-line treatment, highlighting the importance of biomarker-based approaches for immunotherapy in gastric cancer. CLINICAL TRIAL REGISTRATION NCT03751761.
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Affiliation(s)
- Keun Wook Lee
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Republic of Korea
| | - Da Young Zang
- Division of Hematology-Oncology, Department of Internal Medicine, Hallym University Sacred Heart Hospital, Hallym University College of Medicine, Anyang, Republic of Korea
| | - Hyung-Don Kim
- Departmentof Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Jin-Won Kim
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Republic of Korea
| | - Bum Jun Kim
- Division of Hematology-Oncology, Department of Internal Medicine, Hallym University Sacred Heart Hospital, Hallym University College of Medicine, Anyang, Republic of Korea
| | - Yoon-Koo Kang
- Departmentof Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Min-Hee Ryu
- Departmentof Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
| | - Hark Kyun Kim
- Center for Gastric Cancer, National Cancer Center, Goyang, Republic of Korea.
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13
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Qi T, Chang X, Wang Y. Multi-Omics Pan-Cancer Profiling of HSD17B10 Unveils Its Prognostic Potential, Metabolic Regulation, and Immune Microenvironment Interactions. BIOLOGY 2025; 14:567. [PMID: 40427756 PMCID: PMC12108609 DOI: 10.3390/biology14050567] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/18/2025] [Revised: 05/14/2025] [Accepted: 05/15/2025] [Indexed: 05/29/2025]
Abstract
This study systematically analyzed the expression and clinical significance of Hydroxysteroid 17-beta dehydrogenase type 10 (HSD17B10) in 33 cancers by integrating TCGA, GTEx, and other multi-omics databases. HSD17B10 was highly expressed in 14 cancers, like GBM and LGG, but low in 5, such as KIRC. Its expression correlated closely with overall survival (OS) and disease-free survival (DFS). In GBM-LGG, LGG, and other cancers, high HSD17B10 expression was linked to lower survival rates, indicating that it could be an independent prognostic marker. HSD17B10 also had a two-way relationship with the tumor's immune microenvironment. In cancers such as GBM-LGG, high expression correlated positively with immune/stromal scores. However, in most cancers like LUAD, it was negatively associated with B- and T-cell infiltration. Epigenetic analysis showed that low methylation in the HSD17B10 promoter region might drive its high expression in tumors such as SARC, and specific methylation sites (e.g., CG26323797) were significantly related to patient survival. Functional enrichment analysis revealed that HSD17B10 participated in tumor progression by regulating oxidative phosphorylation, mitochondrial metabolism, and RNA methylation. Single-cell and spatial transcriptome data further demonstrated that HSD17B10 had a cell-type-specific expression pattern in colorectal cancer. This study provides a theoretical basis for HSD17B10 as a pan-cancer prognostic marker and therapeutic target.
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Affiliation(s)
| | - Xiao Chang
- School of Statistics and Applied Mathematics, Anhui University of Finance and Economics, Bengbu 233010, China;
| | - Yiming Wang
- School of Statistics and Applied Mathematics, Anhui University of Finance and Economics, Bengbu 233010, China;
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14
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Zhou Y, Lu Y, Czubayko F, Chen J, Zheng S, Mo H, Liu R, Weber GF, Grützmann R, Pilarsky C, David P. Identification of Cancer Associated Fibroblasts Related Genes Signature to Facilitate Improved Prediction of Prognosis and Responses to Therapy in Patients with Pancreatic Cancer. Int J Mol Sci 2025; 26:4876. [PMID: 40430018 PMCID: PMC12112120 DOI: 10.3390/ijms26104876] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2025] [Revised: 04/30/2025] [Accepted: 05/08/2025] [Indexed: 05/29/2025] Open
Abstract
Pancreatic cancer (PC) is highly aggressive, with a 5-year survival rate of 12.8%, making early detection vital. However, non-specific symptoms and precursor lesions complicate diagnosis. Existing tools for the early detection of PC are limited. CAFs are crucial in cancer progression, invasion, and metastasis, yet their role in PC is poorly understood. This study analyzes mRNA data from PC samples to identify CAF-related genes and drugs for PC treatment using algorithms like EPIC, xCell, MCP-counter, and TIDE to quantify CAF infiltration. Weighted gene co-expression network analysis (WGCNA) identified 26 hub genes. Our analyses revealed eight prognostic genes, leading to establishing a six-gene model for assessing prognosis. Correlation analysis showed that the CAF risk score correlates with CAF infiltration and related markers. We also identified six potential drugs, observing significant differences between high-CAF and low-CAF risk groups. High CAF risk scores were associated with lower responses to immunotherapy and higher tumor mutation burdens. GSEA indicated that these scores are enriched in tumor microenvironment pathways. In summary, these six model genes can predict overall survival and responses to chemotherapy and immunotherapy for pancreatic cancer, offering valuable insights for future clinical strategies.
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Affiliation(s)
- Yong Zhou
- Department of Surgery, University Hospital Erlangen, Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany; (Y.Z.); (Y.L.); (F.C.); (J.C.); (S.Z.); (H.M.); (R.L.); (G.F.W.); (R.G.)
| | - Yanxi Lu
- Department of Surgery, University Hospital Erlangen, Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany; (Y.Z.); (Y.L.); (F.C.); (J.C.); (S.Z.); (H.M.); (R.L.); (G.F.W.); (R.G.)
| | - Franziska Czubayko
- Department of Surgery, University Hospital Erlangen, Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany; (Y.Z.); (Y.L.); (F.C.); (J.C.); (S.Z.); (H.M.); (R.L.); (G.F.W.); (R.G.)
| | - Jisheng Chen
- Department of Surgery, University Hospital Erlangen, Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany; (Y.Z.); (Y.L.); (F.C.); (J.C.); (S.Z.); (H.M.); (R.L.); (G.F.W.); (R.G.)
| | - Shuwen Zheng
- Department of Surgery, University Hospital Erlangen, Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany; (Y.Z.); (Y.L.); (F.C.); (J.C.); (S.Z.); (H.M.); (R.L.); (G.F.W.); (R.G.)
| | - Huaqing Mo
- Department of Surgery, University Hospital Erlangen, Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany; (Y.Z.); (Y.L.); (F.C.); (J.C.); (S.Z.); (H.M.); (R.L.); (G.F.W.); (R.G.)
| | - Rui Liu
- Department of Surgery, University Hospital Erlangen, Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany; (Y.Z.); (Y.L.); (F.C.); (J.C.); (S.Z.); (H.M.); (R.L.); (G.F.W.); (R.G.)
| | - Georg F. Weber
- Department of Surgery, University Hospital Erlangen, Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany; (Y.Z.); (Y.L.); (F.C.); (J.C.); (S.Z.); (H.M.); (R.L.); (G.F.W.); (R.G.)
- Deutsches Zentrum für Immuntherapie, Universitätsklinikum Erlangen, Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany
- Bavarian Cancer Research Center (BZKF), 91052 Erlangen, Germany
| | - Robert Grützmann
- Department of Surgery, University Hospital Erlangen, Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany; (Y.Z.); (Y.L.); (F.C.); (J.C.); (S.Z.); (H.M.); (R.L.); (G.F.W.); (R.G.)
- Deutsches Zentrum für Immuntherapie, Universitätsklinikum Erlangen, Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany
- Bavarian Cancer Research Center (BZKF), 91052 Erlangen, Germany
| | - Christian Pilarsky
- Department of Surgery, University Hospital Erlangen, Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany; (Y.Z.); (Y.L.); (F.C.); (J.C.); (S.Z.); (H.M.); (R.L.); (G.F.W.); (R.G.)
| | - Paul David
- Department of Surgery, University Hospital Erlangen, Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany; (Y.Z.); (Y.L.); (F.C.); (J.C.); (S.Z.); (H.M.); (R.L.); (G.F.W.); (R.G.)
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15
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Hushmandi K, Imani Fooladi AA, Reiter RJ, Farahani N, Liang L, Aref AR, Nabavi N, Alimohammadi M, Liu L, Sethi G. Next-generation immunotherapeutic approaches for blood cancers: Exploring the efficacy of CAR-T and cancer vaccines. Exp Hematol Oncol 2025; 14:75. [PMID: 40382583 DOI: 10.1186/s40164-025-00662-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2025] [Accepted: 04/25/2025] [Indexed: 05/20/2025] Open
Abstract
Recent advancements in immunotherapy, particularly Chimeric antigen receptor (CAR)-T cell therapy and cancer vaccines, have significantly transformed the treatment landscape for leukemia. CAR-T cell therapy, initially promising in hematologic cancers, faces notable obstacles in solid tumors due to the complex and immunosuppressive tumor microenvironment. Challenges include the heterogeneous immune profiles of tumors, variability in antigen expression, difficulties in therapeutic delivery, T cell exhaustion, and reduced cytotoxic activity at the tumor site. Additionally, the physical barriers within tumors and the immunological camouflage used by cancer cells further complicate treatment efficacy. To overcome these hurdles, ongoing research explores the synergistic potential of combining CAR-T cell therapy with cancer vaccines and other therapeutic strategies such as checkpoint inhibitors and cytokine therapy. This review describes the various immunotherapeutic approaches targeting leukemia, emphasizing the roles and interplay of cancer vaccines and CAR-T cell therapy. In addition, by discussing how these therapies individually and collectively contribute to tumor regression, this article aims to highlight innovative treatment paradigms that could enhance clinical outcomes for leukemia patients. This integrative approach promises to pave the way for more effective and durable treatment strategies in the oncology field. These combined immunotherapeutic strategies hold great promise for achieving more complete and lasting remissions in leukemia patients. Future research should prioritize optimizing treatment sequencing, personalizing therapeutic combinations based on individual patient and tumor characteristics, and developing novel strategies to enhance T cell persistence and function within the tumor microenvironment. Ultimately, these efforts will advance the development of more effective and less toxic immunotherapeutic interventions, offering new hope for patients battling this challenging disease.
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Affiliation(s)
- Kiavash Hushmandi
- Nephrology and Urology Research Center, Clinical Sciences Institute, Baqiyatallah University of Medical Sciences, Tehran, Islamic Republic of Iran.
| | - Abbas Ali Imani Fooladi
- Applied Microbiology Research Center, Biomedicine Technologies Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Russel J Reiter
- Department of Cell Systems and Anatomy, UT Health San Antonio, San Antonio, TX, 78229, USA
| | - Najma Farahani
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Liping Liang
- Guangzhou Key Laboratory of Digestive Diseases, Department of Gastroenterology and Hepatology, Guangzhou Digestive Disease Center, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, 510180, China
| | - Amir Reza Aref
- Department of Vitro Vision, DeepkinetiX, Inc, Boston, MA, USA
| | | | - Mina Alimohammadi
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Le Liu
- Integrated Clinical Microecology Center, Shenzhen Hospital, Southern Medical University, Shenzhen, 518000, China.
- Department of Gastroenterology, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, China.
| | - Gautam Sethi
- Department of Pharmacology and NUS Centre for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore.
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16
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Goto N, Agudo J, Yilmaz ÖH. Early immune evasion in colorectal cancer: interplay between stem cells and the tumor microenvironment. Trends Cancer 2025:S2405-8033(25)00112-8. [PMID: 40382216 DOI: 10.1016/j.trecan.2025.04.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2025] [Revised: 04/23/2025] [Accepted: 04/24/2025] [Indexed: 05/20/2025]
Abstract
Most colorectal cancers (CRCs) are characterized by a low mutational burden and an immune-cold microenvironment, limiting the efficacy of immune checkpoint blockade (ICB) therapies. While advanced tumors exhibit diverse immune evasion mechanisms, emerging evidence suggests that aspects of immune escape arise much earlier, within precancerous lesions. In this review, we discuss how early driver mutations and epigenetic alterations contribute to the establishment of an immunosuppressive microenvironment in CRC. We also highlight the dynamic crosstalk between cancer cells, stromal niche cells, and immune cells driving immune evasion and liver metastasis. A deeper understanding of these early events may guide the development of more effective preventive and therapeutic strategies for CRC.
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Affiliation(s)
- Norihiro Goto
- Joan and Sanford I. Weill Department of Medicine, Division of Gastroenterology & Hepatology, Weill Cornell Medicine, Cornell University, New York, NY 10021, USA; Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, Cornell University, New York, NY 10021, USA.
| | - Judith Agudo
- Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Immunology, Harvard Medical School, Boston, MA 02215, USA; Ludwig Center at Harvard, Boston, MA 02215, USA; Parker Institute for Cancer Immunotherapy at Dana-Farber Cancer Institute, Boston, MA 02215, USA; New York Stem Cell Foundation, New York, NY 10019, USA
| | - Ömer H Yilmaz
- Department of Biology, The David H. Koch Institute for Integrative Cancer Research at MIT, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA; Department of Pathology, Beth Israel Deaconess Hospital and Harvard Medical School, Boston, MA 02114, USA; Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
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17
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Liu J, Su Y, Zhang C, Dong H, Yu R, Yang X, Tian Y, Feng Y, Zhang J, Shi M, Wang C, Li W, Liu J, He L, Yang X, Liu H. NCOA3 impairs the efficacy of anti-PD-L1 therapy via HSP90α/EZH2/CXCL9 axis in colon cancer. Int Immunopharmacol 2025; 155:114579. [PMID: 40215778 DOI: 10.1016/j.intimp.2025.114579] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2024] [Revised: 03/19/2025] [Accepted: 03/27/2025] [Indexed: 04/29/2025]
Abstract
Immune checkpoint inhibitors (ICIs) have revolutionized colon cancer treatment, but their efficacy is largely restricted by the limited presence of CD8+ cytotoxic T lymphocytes (CTLs). However, the specific genetic alterations that impact the CD8+ CTL infiltration in colon cancer remain poorly understood. Here, we analyzed clinical and multi-omics data from the Memorial Sloan-Kettering Cancer Center (MSKCC) ICIs-treated and The Cancer Genome Atlas (TCGA) colon adenocarcinoma (COAD) cohorts to screen the key mutations that may influence the efficacy of immunotherapy. We found that patients with NCOA3 mutations exhibit better response to immunotherapy and higher CD8+ CTL infiltration. In vitro and in vivo experiments revealed that mutant NCOA3 increases the efficacy of anti-PD-L1 and CD8+ CTL recruitment by upregulating C-X-C motif chemokine ligand 9 (CXCL9), which is dependent on its impaired intrinsic histone acetyltransferase activity. Mechanistically, wild-type NCOA3 as histone acetyltransferase upregulates Heat shock protein 90 alpha (HSP90α) by enhancing histone H3 lysine 27 acetylation (H3K27ac) at its promoter region. Increased HSP90α stabilizes Enhancer of zeste homolog 2 (EZH2), which then increase the histone H3 lysine 27 trimethylation (H3K27me3) at the CXCL9 promoter region, thereby suppressing the expression of CXCL9. Targeted inhibition of NCOA3 by small molecular inhibitor SI-2 improves the efficacy of PD-L1 blockade therapy. NCOA3 could serve as a novel biomarker and potential target to improve the efficacy of immunotherapy.
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Affiliation(s)
- Jiaqi Liu
- Department of Clinical Laboratory, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China
| | - Yixi Su
- Department of Clinical Laboratory, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China
| | - Chi Zhang
- Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Department of General Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China
| | - Haiyan Dong
- Department of Clinical Laboratory, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China
| | - Runfeng Yu
- Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Department of General Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China
| | - Xin Yang
- Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Department of General Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China
| | - Yu Tian
- Department of Clinical Laboratory, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China
| | - Yanchun Feng
- Department of Clinical Laboratory, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China
| | - Jingdan Zhang
- Department of Clinical Laboratory, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China
| | - Mengchen Shi
- Department of Clinical Laboratory, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China
| | - Chen Wang
- Department of Clinical Laboratory, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China
| | - Weiqian Li
- Department of Clinical Laboratory, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China
| | - Jun Liu
- Department of Clinical Laboratory, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China
| | - Lingyuan He
- Department of Clinical Laboratory, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China
| | - Xiangling Yang
- Department of Clinical Laboratory, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China.
| | - Huanliang Liu
- Department of Clinical Laboratory, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China.
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18
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Zaidi N, Jaffee EM, Yarchoan M. Recent advances in therapeutic cancer vaccines. Nat Rev Cancer 2025:10.1038/s41568-025-00820-z. [PMID: 40379970 DOI: 10.1038/s41568-025-00820-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/04/2025] [Indexed: 05/19/2025]
Abstract
The success of cancer prevention vaccines targeting cancer-causing viruses has drastically reduced cancer mortality worldwide. However, the development of therapeutic cancer vaccines, which aim to elicit an immune response directly against cancer cells, has faced notable clinical setbacks. In this Review, we explore lessons learned from past cancer vaccine trials and how the field has progressed into an era of renewed promise. Previous vaccines primarily targeted tumour-associated antigens and were mainly tested as monotherapies in late-stage cancers. In contrast, contemporary vaccines focus on targeting tumour-specific antigens (neoantigens) and are showing initial evidence of clinical efficacy, particularly in early-stage cancers and precancers when combined with immune checkpoint inhibitors. Advances in tumour profiling and novel vaccine platforms have enhanced vaccine specificity and potency. We discuss recent clinical trials of therapeutic cancer vaccines and outline future directions for the field.
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Affiliation(s)
- Neeha Zaidi
- Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Johns Hopkins Bloomberg Kimmel Institute for Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA
| | - Elizabeth M Jaffee
- Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
- Johns Hopkins Bloomberg Kimmel Institute for Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA.
| | - Mark Yarchoan
- Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
- Johns Hopkins Bloomberg Kimmel Institute for Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA.
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19
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Sun F, Gao X, Wang W, Zhao X, Zhang J, Zhu Y. Predictive biomarkers in the era of immunotherapy for gastric cancer: current achievements and future perspectives. Front Immunol 2025; 16:1599908. [PMID: 40438098 PMCID: PMC12116377 DOI: 10.3389/fimmu.2025.1599908] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2025] [Accepted: 04/24/2025] [Indexed: 06/01/2025] Open
Abstract
Gastric cancer (GC) is one of the primary contributors to cancer-related mortality on a global scale. It holds a position within the top five most prevalent malignancies both in terms of occurrence and fatality rates. Immunotherapy, as a breakthrough cancer treatment, brings new hope for GC patients. Various biomarkers, such as the expression of programmed death ligand-1 (PD-L1), the microsatellite instability (MSI) status, tumor mutational burden (TMB), and Epstein-Barr virus (EBV) infection, demonstrate potential to predict the effectiveness of immunotherapy in treating GC. Nevertheless, each biomarker has its own limitations, which leads to a significant portion of patients continue to be unresponsive to immunotherapy. With the understanding of the tumor immune microenvironment (TIME), genome sequencing technology, and recent advances in molecular biology, new molecular markers, such as POLE/POLD1mutations, circulating tumor DNA, intestinal flora, lymphocyte activation gene 3 (LAG-3), and lipid metabolism have emerged. This review aims to consolidate clinical evidence to offer a thorough comprehension of the existing and emerging biomarkers. We discuss the mechanisms, prospects of application, and limitations of each biomarker. We anticipate that this review will open avenues for fresh perspectives in the investigation of GC immunotherapy biomarkers and promote the precise choice of treatment modalities for gastric cancer patients, thereby advancing precision immuno-oncology endeavors.
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Affiliation(s)
- Fujing Sun
- Department of Pathology, Affiliated Cancer Hospital of Dalian University of Technology (Liaoning Cancer Hospital and Institute, Cancer Hospital of China Medical University), Shenyang, China
| | - Xiaozhuo Gao
- Department of Pathology, Affiliated Cancer Hospital of Dalian University of Technology (Liaoning Cancer Hospital and Institute, Cancer Hospital of China Medical University), Shenyang, China
| | - Wentao Wang
- Department of Gastric Surgery, Affiliated Cancer Hospital of Dalian University of Technology (Liaoning Cancer Hospital and Institute, Cancer Hospital of China Medical University), Shenyang, China
| | - Xiaoyan Zhao
- Department of Gynecology, Affiliated Cancer Hospital of Dalian University of Technology (Liaoning Cancer Hospital and Institute, Cancer Hospital of China Medical University), Shenyang, China
- Graduate School, Dalian Medical University, Dalian, China
| | - Jingdong Zhang
- Department of Gastroenterology, Affiliated Cancer Hospital of Dalian University of Technology (Liaoning Cancer Hospital and Institute, Cancer Hospital of China Medical University), Shenyang, China
| | - Yanmei Zhu
- Department of Pathology, Affiliated Cancer Hospital of Dalian University of Technology (Liaoning Cancer Hospital and Institute, Cancer Hospital of China Medical University), Shenyang, China
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20
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Lakbir S, de Wit R, de Bruijn I, Kundra R, Madupuri R, Gao J, Schultz N, Meijer GA, Heringa J, Fijneman RJA, Abeln S. Tumor break load quantitates structural variant-associated genomic instability with biological and clinical relevance across cancers. NPJ Precis Oncol 2025; 9:140. [PMID: 40369102 PMCID: PMC12078582 DOI: 10.1038/s41698-025-00922-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2024] [Accepted: 04/24/2025] [Indexed: 05/16/2025] Open
Abstract
While structural variants (SVs) are a clear sign of genomic instability, they have not been systematically quantified per patient since declining costs have only recently enabled large-scale profiling. Therefore, the biological and clinical impact of high numbers of SVs in patients is unknown. We introduce tumor break load (TBL), defined as the sum of unbalanced SVs, as a measure for SV-associated genomic instability. Using pan-cancer data from TCGA, PCAWG, and CCLE, we show that a high TBL is associated with significant changes in gene expression in 26/31 cancer types that consistently involve upregulation of DNA damage repair and downregulation of immune response pathways. Patients with a high TBL show a higher risk of recurrence and shorter median survival times for 5/15 cancer types. Our data demonstrate that TBL is a biologically and clinically relevant feature of genomic instability that may aid patient prognostication and treatment stratification. For the datasets analyzed in this study, TBL has been made available in cBioPortal.
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Affiliation(s)
- Soufyan Lakbir
- Bioinformatics Section, Department of Computer Science, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
- Translational Gastrointestinal Oncology Group, Department of Pathology, Netherlands Cancer Institute, Amsterdam, The Netherlands
- AI Technology for Life Group, Department of Information and Computing Science; Department of Biology, Utrecht University, Utrecht, The Netherlands
| | - Renske de Wit
- Translational Gastrointestinal Oncology Group, Department of Pathology, Netherlands Cancer Institute, Amsterdam, The Netherlands
- AI Technology for Life Group, Department of Information and Computing Science; Department of Biology, Utrecht University, Utrecht, The Netherlands
| | - Ino de Bruijn
- Memorial Sloan Kettering Cancer Center, New York City, NY, USA
| | - Ritika Kundra
- Memorial Sloan Kettering Cancer Center, New York City, NY, USA
| | | | - Jianjiong Gao
- Memorial Sloan Kettering Cancer Center, New York City, NY, USA
| | | | - Gerrit A Meijer
- Translational Gastrointestinal Oncology Group, Department of Pathology, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Jaap Heringa
- Bioinformatics Section, Department of Computer Science, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
| | - Remond J A Fijneman
- Translational Gastrointestinal Oncology Group, Department of Pathology, Netherlands Cancer Institute, Amsterdam, The Netherlands.
| | - Sanne Abeln
- Bioinformatics Section, Department of Computer Science, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
- AI Technology for Life Group, Department of Information and Computing Science; Department of Biology, Utrecht University, Utrecht, The Netherlands.
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21
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Kong L, Yiu CH, Lu CY. Effectiveness and Safety of Immune Checkpoint Inhibitors in Colorectal Cancer: A Systematic Review of Real-World Studies. Curr Oncol Rep 2025:10.1007/s11912-025-01676-0. [PMID: 40358904 DOI: 10.1007/s11912-025-01676-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/09/2025] [Indexed: 05/15/2025]
Abstract
PURPOSE OF REVIEW Immune checkpoint inhibitors (ICIs) have demonstrated significant efficacy in the treatment of colorectal cancer (CRC). However, most evidence has come from clinical trials with strict eligibility criteria. Understanding real-world effectiveness and safety of ICIs in CRC is important to guide routine clinical practice across diverse populations. RECENT FINDINGS A systematic review following PRISMA guidelines was conducted to identify observational studies evaluating ICI-based regimens compared to conventional or combination therapies in patients with CRC. Three databases (MEDLINE, Embase, and Scopus) were searched from inception through March 15, 2025. Eligible studies reported at least one efficacy outcome (e.g., progression-free survival [PFS], overall survival [OS], etc.) and/or safety outcome (e.g., adverse events) among real-world populations with CRC treated with ICIs. Study quality was assessed using the Newcastle-Ottawa Scale, and a narrative synthesis was performed to summarize the key findings. Eleven real-world studies met the inclusion criteria, encompassing data from 2,049 patients. In MSI-H/dMMR metastatic CRC, real-world findings aligned with the survival benefits observed in clinical trials, demonstrating improved PFS and OS compared to conventional therapies. For MSS/pMMR metastatic CRC, combining ICIs with other agents (e.g., tyrosine kinase inhibitors or chemotherapy) showed improvements but yielded conflicting results. Overall, the safety profiles were comparable to conventional therapies, with treatment-related adverse events occurring at similar rates. Real-world evidence supports the efficacy of ICI monotherapy in MSI-H/dMMR metastatic CRC and suggests potential benefits of ICI-based combination therapies in MSS/pMMR metastatic CRC. However, most of the data are derived from small, single-center cohorts, which limit their generalizability. Further multi-center studies are needed, especially to assess the efficacy of ICI-based combination therapies in the broader CRC population.
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Affiliation(s)
- Leping Kong
- The University of Sydney School of Pharmacy, Camperdown, NSW, Australia
- Kolling Institute, Faculty of Medicine and Health, The University of Sydney and the Northern Sydney Local Health District, Sydney, NSW, Australia
| | - Chin Hang Yiu
- The University of Sydney School of Pharmacy, Camperdown, NSW, Australia
- Kolling Institute, Faculty of Medicine and Health, The University of Sydney and the Northern Sydney Local Health District, Sydney, NSW, Australia
| | - Christine Y Lu
- The University of Sydney School of Pharmacy, Camperdown, NSW, Australia.
- Kolling Institute, Faculty of Medicine and Health, The University of Sydney and the Northern Sydney Local Health District, Sydney, NSW, Australia.
- Department of Pharmacy, Royal North Shore Hospital, St Leonards, New South Wales, Australia.
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22
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Saito S, Kato S, Arai U, En A, Tsunezumi J, Mizushima T, Tateishi K, Adachi N. HR eye & MMR eye: one-day assessment of DNA repair-defective tumors eligible for targeted therapy. Nat Commun 2025; 16:4239. [PMID: 40355434 PMCID: PMC12069580 DOI: 10.1038/s41467-025-59462-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2024] [Accepted: 04/22/2025] [Indexed: 05/14/2025] Open
Abstract
Homologous recombination (HR) and mismatch repair (MMR) act as guardians of the human genome, and defects in HR or MMR are causative in at least a quarter of all malignant tumors. Although these DNA repair-deficient tumors are eligible for effective targeted therapies, fully reliable diagnostic strategies based on functional assay have yet to be established, potentially limiting safe and proper application of the molecular targeted drugs. Here we show that transient transfection of artificial DNA substrates enables ultrarapid detection of HR and MMR. This finding led us to develop a diagnostic strategy that can determine the cellular HR/MMR status within one day without the need for control cells or tissues. Notably, the accuracy of this method allowed the discovery of a pathogenic RAD51D mutation, which was missed by existing companion diagnostic tests. Our methods, termed HR eye and MMR eye, are applicable to frozen tumor tissues and roughly predict the response to therapy. Overall, the findings presented here could pave the way for accurately assessing malignant tumors with functional defects in HR or MMR, a step forward in accelerating precision medicine.
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Affiliation(s)
- Shinta Saito
- Department of Life and Environmental System Science, Graduate School of Nanobioscience, Yokohama City University, Yokohama, 236-0027, Japan
| | - Shingo Kato
- Department of Clinical Cancer Genomics, Yokohama City University Hospital, Yokohama, 236-0004, Japan
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Yokohama City University, Yokohama, 236-0004, Japan
| | - Usaki Arai
- Department of Life and Environmental System Science, Graduate School of Nanobioscience, Yokohama City University, Yokohama, 236-0027, Japan
| | - Atsuki En
- Department of Life and Environmental System Science, Graduate School of Nanobioscience, Yokohama City University, Yokohama, 236-0027, Japan
| | - Jun Tsunezumi
- Department of Life and Environmental System Science, Graduate School of Nanobioscience, Yokohama City University, Yokohama, 236-0027, Japan
| | - Taichi Mizushima
- Department of Obstetrics and Gynecology, Graduate School of Medicine, Yokohama City University, Yokohama, 236-0004, Japan
| | - Kensuke Tateishi
- Department of Neurosurgery, Graduate School of Medicine, Yokohama City University, Yokohama, 236-0004, Japan
| | - Noritaka Adachi
- Department of Life and Environmental System Science, Graduate School of Nanobioscience, Yokohama City University, Yokohama, 236-0027, Japan.
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23
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Salgia NJ, Dizman N, Pal SK. Of HIFs and hERVs: Neoantigen generation in kidney cancer. Cancer Cell 2025; 43:820-822. [PMID: 40118047 DOI: 10.1016/j.ccell.2025.03.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2025] [Revised: 03/02/2025] [Accepted: 03/02/2025] [Indexed: 03/23/2025]
Abstract
New evidence published in Cell provides insight into the interplay between hypoxia-inducible factor activity and downstream neoantigen production in clear cell renal cell carcinoma (ccRCC). Jiang et al. show that HIF2α regulates expression of immunogenic human endogenous retroelements, with implications for antitumor immunity and immunotherapy responsiveness in ccRCC.
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Affiliation(s)
- Nicholas J Salgia
- Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA; Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, USA
| | - Nazli Dizman
- The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Sumanta K Pal
- Department of Medical Oncology & Therapeutics Research, City of Hope Comprehensive Cancer Center, Duarte, CA, USA.
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24
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Li A, Luo M, Liu X, Wu H, Liu X, Zhang Z, Zhang X. Toll-like receptor 3 activation enhances antitumor immune response in lung adenocarcinoma through NF-κB signaling pathway. Front Immunol 2025; 16:1585747. [PMID: 40406122 PMCID: PMC12095255 DOI: 10.3389/fimmu.2025.1585747] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2025] [Accepted: 04/21/2025] [Indexed: 05/26/2025] Open
Abstract
Background Toll-like receptor 3 (TLR3) is a pattern recognition receptor known to play a crucial role in the immune response to cancer. However, its effect on the efficacy of immunotherapy in lung adenocarcinoma (LUAD) remains unclear. This study aims to investigate the role of TLR3 in LUAD by examining its expression levels, prognostic significance, and impact on immune signaling pathways. Methods We analyzed the impact of TLR3 expression on the prognosis of lung adenocarcinoma patients using data from the Cancer Genome Atlas (TCGA) database and four additional cohorts (GSE72094, GSE30219, GSE50081 and GSE31210). Functional enrichment analyses were performed to compare molecular features between low and high TLR3 expression groups using gene set variation analysis (GSVA). We also examined the correlation between TLR3 and tumor mutation burden (TMB), immune infiltration, and PD-L1 expression. Further experimental validation was conducted using co-culture systems of LUAD cells and peripheral blood mononuclear cells (PBMCs) with PD1 inhibitors, and Western blot analysis to investigate the involvement of NF-κB signaling. Results TLR3 expression was significantly lower in LUAD tissues compared to normal tissues, with high TLR3 expression correlating with better survival outcomes across multiple cohorts. High TLR3 expression was associated with increased TMB and enhanced immune activation. Patients with high TLR3 expression exhibited higher immune checkpoint expression and immune cell infiltration. Experimental results showed that TLR3 agonists increased the susceptibility of LUAD cells to activated PBMCs under PD1 inhibitor therapy, inhibiting cell proliferation, migration, and invasion. Additionally, TLR3 has a strong positive correlation with MHC molecules and upregulated PD-L1 expression. NF-κB was identified as a key regulator of PD-L1 expression, with TLR3 agonists enhancing NF-κB and PD-L1 activity. Conclusion TLR3 enhances the anti-tumor immune response in LUAD by modulating NF-κB signaling and PD-L1 expression, making it a promising prognostic biomarker and therapeutic target. This study highlights the potential of TLR3 to improve immunotherapy outcomes, providing a comprehensive analysis of its role in LUAD and paving the way for novel therapeutic strategies targeting TLR3-mediated pathways.
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Affiliation(s)
- Ang Li
- School of Public Health, North China University of Science and Technology, Tangshan, China
- College of Life Science, North China University of Science and Technology, Tangshan, China
- Hebei Key Laboratory of Occupational Health and Safety for Coal Industry, North China University of Science and Technology, Tangshan, China
| | - Man Luo
- College of Life Science, North China University of Science and Technology, Tangshan, China
| | - Xiyao Liu
- College of Life Science, North China University of Science and Technology, Tangshan, China
| | - Hongjiao Wu
- School of Public Health, North China University of Science and Technology, Tangshan, China
- College of Life Science, North China University of Science and Technology, Tangshan, China
- Hebei Key Laboratory of Occupational Health and Safety for Coal Industry, North China University of Science and Technology, Tangshan, China
| | - Xiaoguang Liu
- College of Life Science, North China University of Science and Technology, Tangshan, China
| | - Zhi Zhang
- Affliated Tangshan Gongren Hospital, North China University of Science and Technology, Tangshan, China
| | - Xuemei Zhang
- School of Public Health, North China University of Science and Technology, Tangshan, China
- College of Life Science, North China University of Science and Technology, Tangshan, China
- Hebei Key Laboratory of Occupational Health and Safety for Coal Industry, North China University of Science and Technology, Tangshan, China
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25
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Awosika JA, Gulley JL, Pastor DM. Deficient Mismatch Repair and Microsatellite Instability in Solid Tumors. Int J Mol Sci 2025; 26:4394. [PMID: 40362635 PMCID: PMC12072705 DOI: 10.3390/ijms26094394] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2025] [Revised: 04/26/2025] [Accepted: 04/27/2025] [Indexed: 05/15/2025] Open
Abstract
The integrity of the genome is maintained by mismatch repair (MMR) proteins that recognize and repair base mismatches and insertion/deletion errors generated during DNA replication and recombination. A defective MMR system results in genome-wide instability and the progressive accumulation of mutations. Tumors exhibiting deficient MMR (dMMR) and/or high levels of microsatellite instability (termed "microsatellite instability high", or MSI-H) have been shown to possess fundamental differences in clinical, pathological, and molecular characteristics, distinguishing them from their "microsatellite stable" (MSS) counterparts. Molecularly, they are defined by a high mutational burden, genetic instability, and a distinctive immune profile. Their distinct genetic and immunological profiles have made dMMR/MSI-H tumors particularly amenable to treatment with immune checkpoint inhibitors (ICIs). The ongoing development of biomarker-driven therapies and the evaluation of novel combinations of immune-based therapies, with or without the use of conventional cytotoxic treatment regimens, continue to refine treatment strategies with the goals of maximizing therapeutic efficacy and survival outcomes in this distinct patient population. Moreover, the resultant knowledge of the mechanisms by which these features are suspected to render these tumors more responsive, overall, to immunotherapy may provide information regarding the potential optimization of this therapeutic approach in tumors with proficient MMR (pMMR)/MSS tumors.
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Affiliation(s)
- Joy A. Awosika
- Gastrointestinal Malignancies Section, Thoracic & GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - James L. Gulley
- Center for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Danielle M. Pastor
- Center for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
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26
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Saxena M, Marron TU, Kodysh J, Finnigan JP, Onkar S, Kaminska A, Tuballes K, Guo R, Sabado RL, Meseck M, O'Donnell TJ, Sebra RP, Parekh S, Galsky MD, Blasquez A, Gimenez G, Bicak M, Cimen Bozkus C, Delbeau-Zagelbaum D, Rodriguez D, Acuna-Villaorduna A, Misiukiewicz KJ, Posner MR, Miles BA, Irie HY, Tiersten A, Doroshow DB, Wolf A, Mandeli J, Brody R, Salazar AM, Gnjatic S, Hammerbacher J, Schadt E, Friedlander P, Rubinsteyn A, Bhardwaj N. PGV001, a Multi-Peptide Personalized Neoantigen Vaccine Platform: Phase I Study in Patients with Solid and Hematologic Malignancies in the Adjuvant Setting. Cancer Discov 2025; 15:930-947. [PMID: 40094414 DOI: 10.1158/2159-8290.cd-24-0934] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2024] [Revised: 12/20/2024] [Accepted: 03/05/2025] [Indexed: 03/19/2025]
Abstract
SIGNIFICANCE The PGV001 platform is feasible, safe, and immunogenic. The OpenVax pipeline predicted immunogenic neoantigens in tumors with wide-ranging mutational burdens. Data from this study prompted three additional PGV001 trials, one in newly diagnosed glioblastoma, one in urothelial cancer in combination with an ICI, and another in prostate cancer.
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Affiliation(s)
- Mansi Saxena
- Vaccine and Cell Therapy Laboratory, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York
- Division of Hematology Oncology, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Thomas U Marron
- Division of Hematology Oncology, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Julia Kodysh
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York
| | - John P Finnigan
- Division of Hematology Oncology, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Sayali Onkar
- Vaccine and Cell Therapy Laboratory, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Anna Kaminska
- Vaccine and Cell Therapy Laboratory, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Kevin Tuballes
- Division of Hematology Oncology, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Ruiwei Guo
- Division of Hematology Oncology, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Rachel Lubong Sabado
- Vaccine and Cell Therapy Laboratory, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Marcia Meseck
- Vaccine and Cell Therapy Laboratory, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Timothy J O'Donnell
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Robert P Sebra
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Samir Parekh
- Division of Hematology Oncology, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Matthew D Galsky
- Division of Hematology Oncology, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Ana Blasquez
- Division of Hematology Oncology, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Gustavo Gimenez
- Division of Hematology Oncology, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Mesude Bicak
- Division of Hematology Oncology, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Cansu Cimen Bozkus
- Vaccine and Cell Therapy Laboratory, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York
- Division of Hematology Oncology, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Daniela Delbeau-Zagelbaum
- Division of Hematology Oncology, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Denise Rodriguez
- Division of Hematology Oncology, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Ana Acuna-Villaorduna
- Division of Hematology Oncology, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Krzysztof J Misiukiewicz
- Division of Hematology Oncology, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Marshall R Posner
- Division of Hematology Oncology, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Brett A Miles
- Division of Hematology Oncology, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York
- Department Otolaryngology Head and Neck Surgery, Northwell Cancer Institute, Northwell Health, New York, New York
| | - Hanna Y Irie
- Division of Hematology Oncology, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Amy Tiersten
- Division of Hematology Oncology, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Deborah B Doroshow
- Division of Hematology Oncology, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Andrea Wolf
- Division of Hematology Oncology, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York
| | - John Mandeli
- Division of Hematology Oncology, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Rachel Brody
- Department of Pathology, Icahn School of Medicine, New York, New York
| | | | - Sacha Gnjatic
- Division of Hematology Oncology, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Jeff Hammerbacher
- Division of Hematology Oncology, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Eric Schadt
- Division of Hematology Oncology, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Philip Friedlander
- Division of Hematology Oncology, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Alexander Rubinsteyn
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York
- Department of Genetics, University of North Carolina, Chapel Hill, North Carolina
| | - Nina Bhardwaj
- Vaccine and Cell Therapy Laboratory, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York
- Division of Hematology Oncology, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York
- Parker Institute of Cancer Immunotherapy, San Francisco, California
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27
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Price T, Lugowska I, Chawla SP, Falchook G, Subbiah V, Monzon JG, Arkenau HT, Hui M, Kuboki Y, Dziadziuszko R, Shibaki R, Hong MH, Tan D, Rocha Lima CM, Wang K, Hindoyan A, Shi W, Wong H, Kistler M, Prenen H. A phase I, open-label, multicentre, first-in-human study to evaluate safety, pharmacokinetics and efficacy of AMG 404, a PD-1 inhibitor, in patients with advanced solid tumours. BMJ Open 2025; 15:e088578. [PMID: 40316348 PMCID: PMC12049887 DOI: 10.1136/bmjopen-2024-088578] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2024] [Accepted: 04/04/2025] [Indexed: 05/04/2025] Open
Abstract
OBJECTIVE To evaluate the safety, tolerability, pharmacokinetics (PK) and preliminary antitumour activity of AMG 404, a fully human IgG1 monoclonal antibody targeting programmed cell death-1, in patients with advanced solid tumours. DESIGN First-in-human phase I study comprising eight dose expansion cohorts, including cohorts with microsatellite instability-high (MSI-H) tumours and non-small cell lung cancer with high programmed death-ligand 1 expression (NSCLC/PDL1-H, tumour proportion score ≥50%). SETTING Conducted across 28 global sites. PARTICIPANTS This study enrolled adult patients with histologically or cytologically confirmed metastatic or locally advanced solid tumours not amenable to curative treatment with surgery or radiation. The inclusion criteria included a life expectancy of >3 months, ≥1 measurable or evaluable lesion per modified Response Evaluation Criteria in Solid Tumours (RECIST) V.1.1, an Eastern Cooperative Oncology Group performance status of ≤2 and adequate haematological, renal and hepatic function. Patients with prior treatment with checkpoint inhibitors, primary brain tumour or untreated or symptomatic brain metastases and leptomeningeal disease and history of other malignancy within the past 2 years were excluded. INTERVENTIONS The planned doses were 240 mg, 480 mg and 1050 mg of AMG 404 administered every 4 weeks (Q4W). PRIMARY AND SECONDARY OUTCOME MEASURES Primary endpoints were dose-limiting toxicities (DLTs), treatment-emergent adverse events, treatment-related adverse events, changes in vital signs and clinical laboratory tests. Secondary endpoints included PK parameters, incidence of antidrug (AMG 404) antibodies and antitumour activity assessed per modified RECIST V.1.1 (objective response, duration of response, progression-free survival (PFS), disease control and duration of stable disease). RESULTS A total of 171 patients were enrolled; 168 were treated. Median (range) follow-up was 36.3 weeks (1.6-137.1). No DLTs were observed. Grade 3 and serious treatment-related adverse events occurred in 16 (9.5%) and 12 (7.1%) patients, respectively. The 480 mg Q4W dose was selected as the recommended phase II dose. AMG 404 serum exposure increased approximately dose proportionally. The objective response rate (80% CI) was 19.6% (15.7-24.1) for the overall population and 36.6% (26.4-47.8) and 30.8% (14.2-52.3) for cohorts with MSI-H tumours (n=41) and NSCLC/PDL1-H (n=13), respectively. The overall disease control rate (80% CI) was 54.8% (49.5-59.9). The median (80% CI) PFS was 3.7 (3.5-4.5) months for the overall population and 14.8 (9.0-not estimable) and 4.4 (2.2-9.7) months for cohorts with MSI-H tumours and NSCLC/PDL1-H, respectively. CONCLUSIONS AMG 404 monotherapy was tolerable at the tested doses, with encouraging antitumour activity observed across tumour types. TRIAL REGISTRATION NUMBER NCT03853109.
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MESH Headings
- Humans
- Female
- Male
- Middle Aged
- Aged
- Adult
- Antibodies, Monoclonal, Humanized/pharmacokinetics
- Antibodies, Monoclonal, Humanized/adverse effects
- Antibodies, Monoclonal, Humanized/therapeutic use
- Antibodies, Monoclonal, Humanized/administration & dosage
- Neoplasms/drug therapy
- Carcinoma, Non-Small-Cell Lung/drug therapy
- Programmed Cell Death 1 Receptor/antagonists & inhibitors
- Lung Neoplasms/drug therapy
- Aged, 80 and over
- Immune Checkpoint Inhibitors/pharmacokinetics
- Immune Checkpoint Inhibitors/adverse effects
- Immune Checkpoint Inhibitors/therapeutic use
- Dose-Response Relationship, Drug
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Affiliation(s)
- Timothy Price
- The Queen Elizabeth Hospital, Woodville, Adelaide, Australia
| | - Iwona Lugowska
- Maria Sklodowska-Curie Institute of Oncology Warsaw, Warszawa, Poland
| | - Sant P Chawla
- Sarcoma Oncology Center, Santa Monica, California, USA
| | - Gerald Falchook
- Sarah Cannon Research Institute at HealthONE, Denver, Colorado, USA
| | - Vivek Subbiah
- University of Texas MD Anderson Cancer Centre, Houston, Texas, USA
| | | | | | - Mun Hui
- Chris O'Brien Lifehouse, Camperdown, New South Wales, Australia
| | | | | | | | - Min Hee Hong
- Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea
| | - Daniel Tan
- National Cancer Centre Singapore, SingHealth, and Duke-NUS Medical School, Singapore
| | | | | | | | - Weibing Shi
- Amgen Inc San Francisco, South San Francisco, California, USA
| | - Hansen Wong
- Amgen Inc San Francisco, South San Francisco, California, USA
| | - Mira Kistler
- Amgen Inc San Francisco, South San Francisco, California, USA
| | - Hans Prenen
- University Hospital Antwerp, Edegem, Antwerp, Belgium
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28
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Seino M, Sano S, Gonai Y, Horikawa S, Nakamura F, Okui Y, Matsukawa J, Sakaki H, Watanabe N, Yamauchi K, Ohta T, Hoshi Y, Suzuki S, Kawai M, Nagase S. Investigation of tumor mutation burden using the comprehensive genomic profiling data of vulvar and vaginal malignant tumors: an observational study using C-CAT database. Int J Clin Oncol 2025; 30:1033-1039. [PMID: 40192944 DOI: 10.1007/s10147-025-02730-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2024] [Accepted: 02/23/2025] [Indexed: 04/23/2025]
Abstract
BACKGROUND This study aimed to reveal the gene alteration and tumor mutation burden (TMB) statuses of vulvar and vaginal malignant tumors in Japan. METHODS We investigated the cancer genomic profiling (CGP) data of 79 patients with vulvar and vaginal cancers. These data were obtained from the Center for Cancer Genomics and Advanced Therapeutics (C-CAT). RESULTS None of the patients had high microsatellite instability. Although 21.9% of the patients with vulvar and vaginal squamous cell carcinoma (SCC) had high TMB, those with other histological types did not. The top single-nucleotide variants (SNVs) in SCC were TERT, TP53, CDKN2A, KMT2D, and NOTCH1. The frequencies of ATRX and PBRM1 were significantly higher in TMB-high SCC than in non-TMB-high SCC. CONCLUSION SCC of the vulva and vagina is expected to have high TMB, and gene alteration status differed between TMB-high and non-TMB-high groups.
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Affiliation(s)
- Manabu Seino
- Department of Obstetrics and Gynecology, Yamagata University Faculty of Medicine, 2-2-2 Iidanishi, Yamagata, 990-9585, Japan.
| | - Shiori Sano
- Department of Obstetrics and Gynecology, Yamagata University Faculty of Medicine, 2-2-2 Iidanishi, Yamagata, 990-9585, Japan
| | - Yuta Gonai
- Department of Obstetrics and Gynecology, Yamagata University Faculty of Medicine, 2-2-2 Iidanishi, Yamagata, 990-9585, Japan
| | - Shota Horikawa
- Department of Obstetrics and Gynecology, Yamagata University Faculty of Medicine, 2-2-2 Iidanishi, Yamagata, 990-9585, Japan
| | - Fumihiro Nakamura
- Department of Obstetrics and Gynecology, Yamagata University Faculty of Medicine, 2-2-2 Iidanishi, Yamagata, 990-9585, Japan
| | - Yosuke Okui
- Department of Obstetrics and Gynecology, Yamagata University Faculty of Medicine, 2-2-2 Iidanishi, Yamagata, 990-9585, Japan
| | - Jun Matsukawa
- Department of Obstetrics and Gynecology, Yamagata University Faculty of Medicine, 2-2-2 Iidanishi, Yamagata, 990-9585, Japan
| | - Hirotsugu Sakaki
- Department of Obstetrics and Gynecology, Yamagata University Faculty of Medicine, 2-2-2 Iidanishi, Yamagata, 990-9585, Japan
| | - Norikazu Watanabe
- Department of Obstetrics and Gynecology, Yamagata University Faculty of Medicine, 2-2-2 Iidanishi, Yamagata, 990-9585, Japan
| | - Keiko Yamauchi
- Department of Obstetrics and Gynecology, Yamagata University Faculty of Medicine, 2-2-2 Iidanishi, Yamagata, 990-9585, Japan
| | - Tsuyoshi Ohta
- Department of Obstetrics and Gynecology, Yamagata University Faculty of Medicine, 2-2-2 Iidanishi, Yamagata, 990-9585, Japan
| | - Yuki Hoshi
- Genetic Counseling Unit, Yamagata University Hospital, Yamagata, Japan
| | - Shuhei Suzuki
- Department of Clinical Oncology, Yamagata Prefecture Shinjo Hospital, Yamagata, Japan
| | - Masaaki Kawai
- Department of Surgery I, Yamagata University Faculty of Medicine, Yamagata, Japan
| | - Satoru Nagase
- Department of Obstetrics and Gynecology, Yamagata University Faculty of Medicine, 2-2-2 Iidanishi, Yamagata, 990-9585, Japan
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29
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Li HJ, Yu ZY, Gao HP, Xu YR, Li XY, Jiang W, Chen D, Yan DM, Yang C, Liu XZ. Inhibiting ADORA1 enhances glioma apoptosis and increases its sensitivity to anti-PD1 therapy. Front Oncol 2025; 15:1545780. [PMID: 40376586 PMCID: PMC12078947 DOI: 10.3389/fonc.2025.1545780] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2024] [Accepted: 04/09/2025] [Indexed: 05/18/2025] Open
Abstract
Introduction Glioma, the primary cancerous tumor of the central nervous system in adults, has a poor outlook. Immune checkpoint blockade therapy has exhibited notable efficacy against various cancer types. Prior research has suggested that the adenosine A1 receptor (ADORA1) facilitates the proliferation of tumors in cancer. Nevertheless, the precise impact of ADORA1 on glioma progression and its influence on anti-programmed death receptor 1 (PD1) therapy, along with the underlying regulatory mechanisms, remain to be fully elucidated. Methods Bioinformatics was used to explore the correlation between ADORA1 expression and glioma prognosis. The effects of ADORA1 on glioma and anti-PD1 therapy were investigated in both laboratory settings and living organisms. Results The results revealed a significant increase in ADORA1 expression in glioma, which was correlated with poor prognosis. Furthermore, ADORA1 inhibition facilitated glioma apoptosis by augmenting kininogen-1 (KNG1). ADORA1 inhibition enhanced T cell recruitment and increased glioma susceptibility to anti-PD1 therapy. Dicussion Our findings indicate that inhibiting ADORA1 can induce apoptosis in glioma cells and increase their sensitivity to anti-PD1 therapy. ADORA1 may serve as a prognostic marker for glioma and a potential target to enhance the effectiveness of anti-PD-1 therapy.
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Affiliation(s)
- Hong-jiang Li
- Department of Neurosurgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Zhi-yun Yu
- Department of Neurosurgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Hua-ping Gao
- Department of Neurosurgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yi-ran Xu
- Henan Key Laboratory of Child Brain Injury and Henan Clinical Research Center for Child Neurological Disorders, Institute of Neuroscience, Third Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Xue-yuan Li
- Department of Neurosurgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Wei Jiang
- The Application Center for Precision Medicine, Academy of Medical Science, Zhengzhou, China
| | - Di Chen
- Department of Neurosurgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Dong-ming Yan
- Department of Neurosurgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Chao Yang
- Department of Neurosurgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Xian-zhi Liu
- Department of Neurosurgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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30
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Wang Y, Han J, Yin S, Yang S, Kang X, Zheng X, Duan L, Li S, Jiang B, Li W, Chen F. Bruton's tyrosine kinase inhibitor zanubrutinib-based regimens in relapsed/refractory primary diffuse large B-cell lymphoma of the central nervous system. Leuk Lymphoma 2025; 66:869-878. [PMID: 39819306 DOI: 10.1080/10428194.2025.2451066] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2024] [Revised: 12/30/2024] [Accepted: 01/04/2025] [Indexed: 01/19/2025]
Abstract
Patients with relapsed/refractory primary central nervous system lymphoma (R/R PCNSL) usually have a poor prognosis and limited treatment options. We respectively reviewed 38 patients with R/R PCNSL treated with zanubrutinib-based regimens in our center. The overall response rate, complete response rate and disease control rate were 76.3%, 47.4% and 92.1%, respectively. The median progression-free survival (PFS) was 31.0 months, the median overall survival (OS) was not reached. Unitivariate analysis by Cox's proportional hazards model revealed that overall response (vs. no response, HR = 0.18, 95%CI:0.07,0.48, p = 0.001), long duration of zanubrutinib (≥6months vs 2-5 months, HR = 0.20, 95%CI:0.06,0.63, p = 0.006) were independent factors for prolonged PFS. The log-rank analysis indicated a prolongation of PFS among patients exhibiting a higher Tumor mutational burden (TMB, ≥14.75muts/Mb) following zanubrutinib-based treatment (p = 0.016). Our data showed promising efficacy with tolerable safety of zanubrutinib-based therapies in patients with R/R PCNSL. Long duration of zanubrutinib may be associated with prolonged PFS.
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MESH Headings
- Humans
- Female
- Male
- Middle Aged
- Lymphoma, Large B-Cell, Diffuse/drug therapy
- Lymphoma, Large B-Cell, Diffuse/mortality
- Lymphoma, Large B-Cell, Diffuse/pathology
- Lymphoma, Large B-Cell, Diffuse/genetics
- Aged
- Central Nervous System Neoplasms/drug therapy
- Central Nervous System Neoplasms/mortality
- Central Nervous System Neoplasms/pathology
- Pyrimidines/administration & dosage
- Pyrimidines/therapeutic use
- Pyrazoles/administration & dosage
- Pyrazoles/therapeutic use
- Adult
- Agammaglobulinaemia Tyrosine Kinase/antagonists & inhibitors
- Piperidines/administration & dosage
- Antineoplastic Combined Chemotherapy Protocols/therapeutic use
- Antineoplastic Combined Chemotherapy Protocols/adverse effects
- Drug Resistance, Neoplasm
- Neoplasm Recurrence, Local/drug therapy
- Neoplasm Recurrence, Local/pathology
- Aged, 80 and over
- Protein Kinase Inhibitors/therapeutic use
- Protein Kinase Inhibitors/administration & dosage
- Retrospective Studies
- Treatment Outcome
- Prognosis
- Mutation
- Tyrosine Kinase Inhibitors
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Affiliation(s)
- Yali Wang
- Department of Neuro-oncology, Cancer Center, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Jiefei Han
- Department of Neuro-oncology, Cancer Center, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Shuo Yin
- Department of Neuro-oncology, Cancer Center, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Shoubo Yang
- Department of Neuro-oncology, Cancer Center, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Xun Kang
- Department of Neuro-oncology, Cancer Center, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Xiaohong Zheng
- Department of Neuro-oncology, Cancer Center, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Ling Duan
- Department of Neuro-oncology, Cancer Center, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Shenglan Li
- Department of Neuro-oncology, Cancer Center, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Bo Jiang
- Department of Neuro-oncology, Cancer Center, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Wenbin Li
- Department of Neuro-oncology, Cancer Center, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Feng Chen
- Department of Neuro-oncology, Cancer Center, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
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31
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Hida T. Genomic profiling and personalized treatment strategies for skin malignancies: findings from the center for cancer genomics and advanced therapeutics database. Int J Clin Oncol 2025; 30:856-866. [PMID: 40156656 DOI: 10.1007/s10147-025-02755-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2025] [Accepted: 03/23/2025] [Indexed: 04/01/2025]
Abstract
Immune checkpoint inhibitors and molecular-targeted therapies have dominated recent cancer treatment. However, these treatments face challenges, such as primary and acquired resistance, indicating that not all patients benefit from them. Therefore, the search for new molecular targets is crucial. In addition, immune checkpoint inhibitors have exhibited racial differences in their effectiveness for certain neoplasms. Hence, understanding the genomic landscape of cancers in various racial groups is important. In Japan, health insurance has covered comprehensive genomic profiling since 2019, and the Center for Cancer Genomics and Advanced Therapeutics (C-CAT) has accumulated genetic abnormalities along with clinical data of patients with various cancers. These data are crucial for advancing cancer research and drug development. This review discusses the genetic abnormalities of the major skin malignancies including melanoma, cutaneous squamous cell carcinoma (cSCC), and extramammary Paget's disease (EMPD), and proposes potential treatment strategies by comparing C-CAT data analysis with other genetic studies. The C-CAT data have emphasized unique genetic alterations in tumors of the Japanese population, particularly racial differences in tumor mutational burden in cutaneous melanoma and cSCC, indicating the importance of personalized treatment strategies that consider racial differences.
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Affiliation(s)
- Tokimasa Hida
- Department of Dermatology, Sapporo Medical University School of Medicine, South 1, West 16, Chuo-Ku, Sapporo, 060-8543, Japan.
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32
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Sawada K, Yamashita R, Sakai SA, Horasawa S, Yoshikawa A, Fujisawa T, Kadowaki S, Kato K, Ueno M, Oki E, Komatsu Y, Chiyoda T, Horita Y, Yasui H, Denda T, Satake H, Esaki T, Satoh T, Takahashi N, Yamazaki K, Matsuhashi N, Nishina T, Takeda H, Ohtsubo K, Ohta T, Tsuji A, Goto M, Kato T, Bando H, Tsuchihara K, Nakamura Y, Yoshino T. Microbiome Landscape and Association with Response to Immune Checkpoint Inhibitors in Advanced Solid Tumors: A SCRUM-Japan MONSTAR-SCREEN Study. CANCER RESEARCH COMMUNICATIONS 2025; 5:857-870. [PMID: 40341952 DOI: 10.1158/2767-9764.crc-24-0543] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/06/2024] [Revised: 02/04/2025] [Accepted: 05/06/2025] [Indexed: 05/11/2025]
Abstract
Although the gut microbiome is associated with cancer development and progression, little is known about the effects of the gut microbiome landscape and the efficacy of immune checkpoint inhibitors (ICI) across cancer types. We investigated the association between the microbiome, clinical features, and ICI efficacy across cancer types in a large nationwide screening project for solid tumors. Among 2,180 patients with advanced solid tumors enrolled in the SCRUM-Japan MONSTAR-SCREEN between October 2019 and September 2021, in the chemotherapy-naïve cohort (n = 817), a high prevalence of oral bacteria was observed in patients using proton pump inhibitors (PPI) and those with upper gastrointestinal cancers, particularly postoperative patients with gastric or pancreatic cancer. Among patients treated with ICIs (n = 333), a high abundance of sequence variants in the gut microbiome was not significantly associated with ICI efficacy across cancer types (HR = 0.94; 95% confidence interval, 0.73-1.21). However, high oral bacteria in feces significantly correlated with a shorter progression-free survival compared with low oral bacteria (median, 4.34 vs. 6.97 months; HR = 1.38; 95% confidence interval, 1.07-1.78). Notably, in patients using PPIs, a higher proportion of oral bacteria influenced progression-free survival outcomes of ICI treatment (median, 3.15 vs. 2.04 months; P = 0.08), unlike in PPI nonusers (median, 7.13 vs. 5.55 months; P = 0.74). This study of the gut microbiome has unveiled significant insights into its landscape and potential impact on ICI efficacy. It highlights that the abundance of oral bacteria in feces may play a critical role in diminishing ICI efficacy among patients using PPIs. SIGNIFICANCE As part of the MONSTAR-SCREEN, a prospective nationwide project for patients with solid tumors, we found that although gut microbiome diversity does not consistently predict ICI efficacy across cancer types, a high level of oral bacteria in the gut is linked to reduced ICI effectiveness, especially in patients using PPIs. These findings highlight the potential clinical impact of microbiome variations on cancer treatment outcomes.
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Affiliation(s)
- Kentaro Sawada
- Department of Medical Oncology, Kushiro Rosai Hospital, Kushiro, Japan
| | - Riu Yamashita
- Division of Translational Informatics, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Japan
- Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan
| | - Shunsuke A Sakai
- Division of Translational Informatics, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Japan
- Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan
| | - Satoshi Horasawa
- Translational Research Support Office, National Cancer Center Hospital East, Kashiwa, Japan
| | - Ayumu Yoshikawa
- Department of Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Takao Fujisawa
- Head and Neck Medical Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Shigenori Kadowaki
- Department of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya, Japan
| | - Ken Kato
- Department of Head and Neck Medical Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Makoto Ueno
- Department of Gastroenterology, Kanagawa Cancer Center, Yokohama, Japan
| | - Eiji Oki
- Department of Surgery and Science, Kyushu University Hospital, Fukuoka, Japan
| | - Yoshito Komatsu
- Department of Cancer Center, Hokkaido University Hospital, Sapporo, Japan
| | - Tatsuyuki Chiyoda
- Department of Obstetrics and Gynecology, Keio University School of Medicine, Tokyo, Japan
| | - Yosuke Horita
- Department of Medical Oncology, Saitama Medical University International Medical Center, Hidaka, Japan
| | - Hisateru Yasui
- Department of Medical Oncology, Kobe City Medical Center General Hospital, Kobe, Japan
| | - Tadamichi Denda
- Department of Gastroenterology, Chiba Cancer Center, Chiba, Japan
| | - Hironaga Satake
- Cancer Treatment Center, Kansai Medical University Hospital, Hirakata, Japan
- Department of Medical Oncology, Kochi Medical School, Nankoku, Japan
| | - Taito Esaki
- Department of Gastrointestinal and Medical Oncology, National Hospital Organization Kyushu Cancer Center, Fukuoka, Japan
| | - Taroh Satoh
- Department of Frontier Science for Cancer and Chemotherapy, Graduate School of Medicine, Osaka University, Suita, Japan
| | - Naoki Takahashi
- Department of Gastroenterology, Saitama Cancer Center, Ina, Japan
| | - Kentaro Yamazaki
- Division of Gastrointestinal Oncology, Shizuoka Cancer Center, Nagaizumi, Japan
| | - Nobuhisa Matsuhashi
- Department of Gastroenterological Surgery and Pediatric Surgery, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Tomohiro Nishina
- Gastrointestinal Medical Oncology, National Hospital Organization Shikoku Cancer Center, Gifu, Japan
| | - Hiroyuki Takeda
- Department of Clinical Oncology, St. Marianna University School of Medicine, Kawasaki, Japan
| | - Koushiro Ohtsubo
- Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan
| | - Takashi Ohta
- Department of Clinical Oncology, Kansai Rosai Hospital, Amagasaki, Japan
| | - Akihito Tsuji
- Department of Clinical Oncology, Kagawa University Hospital, Amagasaki, Japan
| | - Masahiro Goto
- Cancer Chemotherapy Center, Osaka Medical and Pharmaceutical University Hospital, Takatsuki, Japan
| | - Takeshi Kato
- Department of Surgery, National Hospital Organization Osaka National Hospital, Osaka, Japan
| | - Hideaki Bando
- Translational Research Support Office, National Cancer Center Hospital East, Kashiwa, Japan
- Department of Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Katsuya Tsuchihara
- Division of Translational Informatics, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Japan
- Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan
| | - Yoshiaki Nakamura
- Translational Research Support Office, National Cancer Center Hospital East, Kashiwa, Japan
- Department of Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Takayuki Yoshino
- Department of Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan
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Lindberg A, Muhl L, Yu H, Hellberg L, Artursson R, Friedrich J, Backman M, Hekmati N, Mattsson J, Lindskog C, Brunnström H, Botling J, Mezheyeuski A, Broström E, Gulyas M, Kärre K, Isaksson J, Micke P, Strell C. In Situ Detection of Programmed Cell Death Protein 1 and Programmed Death Ligand 1 Interactions as a Functional Predictor for Response to Immune Checkpoint Inhibition in NSCLC. J Thorac Oncol 2025; 20:625-640. [PMID: 39743139 DOI: 10.1016/j.jtho.2024.12.026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2024] [Revised: 12/06/2024] [Accepted: 12/27/2024] [Indexed: 01/04/2025]
Abstract
INTRODUCTION Immune checkpoint inhibitors (ICIs) have transformed lung cancer treatment, yet their effectiveness seem restricted to certain patient subsets. Current clinical stratification on the basis of programmed death ligand 1 (PD-L1) expression offers limited predictive value. Given the mechanism of action, directly detecting spatial programmed cell death protein 1 (PD1)-PD-L1 interactions might yield more precise insights into immune responses and treatment outcomes. METHODS We applied a second-generation in situ proximity ligation assay to detect PD1-PD-L1 interactions in diagnostic tissue samples from 16 different cancer types, a tissue microarray with surgically resected early-stage NSCLC, and finally diagnostic biopsies from 140 patients with advanced NSCLC with and without ICI treatment. RNA sequencing analysis was used to identify potential resistance mechanisms. RESULTS In the early-stage NSCLC, only approximately half of the cases with detectable PD-L1 and PD1 expression exhibited PD1-PD-L1 interactions, with significantly lower levels in EGFR-mutated tumors. Interaction levels varied across cancer types, aligning with reported ICI response rates. In ICI-treated patients with NSCLC, higher PD1-PD-L1 interactions were linked to complete responses and longer survival, outperforming standard PD-L1 expression assays. Patients who did not respond to ICIs despite high PD1-PD-L1 interactions exhibited additional expression of stromal immune mediators (EOMES, HAVCR1/TIM-1, JAML, FCRL1). CONCLUSION Our study proposes a diagnostic shift from static biomarker quantification to assessing active immune pathways, providing more precise ICI treatment. This functional concept applies to tiny lung biopsies and can be extended to further immune checkpoints. Accordingly, our results indicate concerted ICI resistance mechanisms, highlighting the need for combination diagnostics and therapies.
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Affiliation(s)
- Amanda Lindberg
- Department of Immunology, Genetics, and Pathology, Uppsala University, Uppsala, Sweden
| | - Lars Muhl
- Department of Medicine (Huddinge), Karolinska Institutet, Huddinge, Sweden; Centre of Cancer Biomarkers (CCBIO), Department of Clinical Medicine, University of Bergen, Bergen, Norway
| | - Hui Yu
- Department of Immunology, Genetics, and Pathology, Uppsala University, Uppsala, Sweden
| | - Louise Hellberg
- Department of Immunology, Genetics, and Pathology, Uppsala University, Uppsala, Sweden
| | - Rebecca Artursson
- Department of Immunology, Genetics, and Pathology, Uppsala University, Uppsala, Sweden
| | - Jakob Friedrich
- Department of Immunology, Genetics, and Pathology, Uppsala University, Uppsala, Sweden
| | - Max Backman
- Department of Immunology, Genetics, and Pathology, Uppsala University, Uppsala, Sweden
| | - Neda Hekmati
- Department of Immunology, Genetics, and Pathology, Uppsala University, Uppsala, Sweden
| | - Johanna Mattsson
- Department of Immunology, Genetics, and Pathology, Uppsala University, Uppsala, Sweden
| | - Cecilia Lindskog
- Department of Immunology, Genetics, and Pathology, Uppsala University, Uppsala, Sweden
| | | | - Johan Botling
- Department of Immunology, Genetics, and Pathology, Uppsala University, Uppsala, Sweden; Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Artur Mezheyeuski
- Vall d'Hebron Institute of Oncology, Molecular Oncology Group, Barcelona, Spain; Vall d'Hebron Institute of Research, Barcelona, Spain
| | - Erika Broström
- Department of Immunology, Genetics, and Pathology, Uppsala University, Uppsala, Sweden; Department of Medical Sciences, Uppsala University, Uppsala, Sweden
| | - Miklos Gulyas
- Department of Immunology, Genetics, and Pathology, Uppsala University, Uppsala, Sweden
| | - Klas Kärre
- Department of Microbiology, Cell and Tumor Biology, Karolinska Institutet, Stockholm, Sweden
| | - Johan Isaksson
- Department of Immunology, Genetics, and Pathology, Uppsala University, Uppsala, Sweden
| | - Patrick Micke
- Department of Immunology, Genetics, and Pathology, Uppsala University, Uppsala, Sweden
| | - Carina Strell
- Department of Immunology, Genetics, and Pathology, Uppsala University, Uppsala, Sweden; Centre of Cancer Biomarkers (CCBIO), Department of Clinical Medicine, University of Bergen, Bergen, Norway.
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Lee SW, Yun JS, Kim YJ, Jeong S, Noh JE, Kim HO, Cho HJ, Park CK, Oh IJ, Cho JH. Progressive accumulation of circulating CD27 -CD28 - effector/memory CD8 + T cells in patients with lung cancer blunts responses to immune checkpoint inhibitor therapy. Exp Mol Med 2025:10.1038/s12276-025-01448-7. [PMID: 40307573 DOI: 10.1038/s12276-025-01448-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2024] [Revised: 12/30/2024] [Accepted: 03/03/2025] [Indexed: 05/02/2025] Open
Abstract
Suppression of tumor-reactive CD8+ T cells is common within the tumor microenvironment. However, little is known about how tumors systemically affect the overall CD8+ T cell compartment. Here we demonstrate that peripheral blood CD8+ T cells from patients with lung cancer showed altered compositions particularly within CD45RA-CCR7- effector memory subpopulation. Specifically, patients with lung cancer exhibited increased frequency of more differentiated effector memory cells, which are less susceptible to T cell-receptor-induced proliferation. Further analysis using single-cell RNA sequencing revealed that these alterations were correlated with reduced quiescence and increased spontaneous activation at a systemic level, indicative of homeostatic dysregulation of the entire CD8+ T cell population. This phenomenon was found to be correlated with a poor clinical response to immune checkpoint inhibitor therapy across four independent cohorts, consisting of a total of 224 patients with lung cancer. These findings suggest that lung cancers continue to counteract potentially tumor-reactive CD8+ T cells by inducing homeostatic dysregulation of the entire CD8+ T cell compartment systematically.
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Affiliation(s)
- Sung-Woo Lee
- Department of Microbiology and Immunology, Chonnam National University Medical School, Gwangju, Republic of Korea
- Medical Research Center for Combinatorial Tumor Immunotherapy, Chonnam National University Medical School, Gwangju, Republic of Korea
| | - Ju Sik Yun
- Department of Thoracic and Cardiovascular Surgery, Chonnam National University Medical School, Hwasun Hospital, Gwangju, Republic of Korea
| | - Young Ju Kim
- Department of Microbiology and Immunology, Chonnam National University Medical School, Gwangju, Republic of Korea
- Medical Research Center for Combinatorial Tumor Immunotherapy, Chonnam National University Medical School, Gwangju, Republic of Korea
- National Immunotherapy Innovation Center, Chonnam National University Medical School, Gwangju, Republic of Korea
- BioMedical Sciences Graduate Program, Chonnam National University Medical School, Gwangju, Republic of Korea
| | - Saei Jeong
- Department of Microbiology and Immunology, Chonnam National University Medical School, Gwangju, Republic of Korea
- Medical Research Center for Combinatorial Tumor Immunotherapy, Chonnam National University Medical School, Gwangju, Republic of Korea
- National Immunotherapy Innovation Center, Chonnam National University Medical School, Gwangju, Republic of Korea
- BioMedical Sciences Graduate Program, Chonnam National University Medical School, Gwangju, Republic of Korea
| | - Jeong Eun Noh
- Department of Microbiology and Immunology, Chonnam National University Medical School, Gwangju, Republic of Korea
- Medical Research Center for Combinatorial Tumor Immunotherapy, Chonnam National University Medical School, Gwangju, Republic of Korea
- National Immunotherapy Innovation Center, Chonnam National University Medical School, Gwangju, Republic of Korea
- BioMedical Sciences Graduate Program, Chonnam National University Medical School, Gwangju, Republic of Korea
| | - Hee-Ok Kim
- Selecxine Inc., Seoul, Republic of Korea
| | - Hyun-Ju Cho
- Department of Internal Medicine, Chonnam National University Medical School, Hwasun Hospital, Gwangju, Republic of Korea
| | - Cheol-Kyu Park
- Department of Internal Medicine, Chonnam National University Medical School, Hwasun Hospital, Gwangju, Republic of Korea
| | - In-Jae Oh
- Department of Internal Medicine, Chonnam National University Medical School, Hwasun Hospital, Gwangju, Republic of Korea.
| | - Jae-Ho Cho
- Department of Microbiology and Immunology, Chonnam National University Medical School, Gwangju, Republic of Korea.
- Medical Research Center for Combinatorial Tumor Immunotherapy, Chonnam National University Medical School, Gwangju, Republic of Korea.
- National Immunotherapy Innovation Center, Chonnam National University Medical School, Gwangju, Republic of Korea.
- BioMedical Sciences Graduate Program, Chonnam National University Medical School, Gwangju, Republic of Korea.
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Che S, Zhang Y, Xu H, Shi J, Hou Y. TBB inhibits CK2/PD-L1/EGFR pathway-mediated tumor progression. Eur J Pharmacol 2025; 999:177689. [PMID: 40311835 DOI: 10.1016/j.ejphar.2025.177689] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2025] [Revised: 04/18/2025] [Accepted: 04/29/2025] [Indexed: 05/03/2025]
Abstract
The expression of PD-L1 on cancer cells facilitates tumor immune escape by binding to PD-1 on T cells, thereby inhibiting T cell activity. However, the role of intracellular PD-L1 signaling in tumor progression remains unclear. In this study, we demonstrate that CK2 induces PD-L1 phosphorylation at Thr-285, which enhances PD-L1 protein stability. This phosphorylation disrupts the interaction between LC3B and PD-L1, inhibiting PD-L1 degradation via autophagy. Furthermore, PD-L1-T285 phosphorylation promotes EGFR binding to PD-L1, leading to activation of EGFR downstream signaling. This activation drives non-small cell lung cancer (NSCLC) cell proliferation, migration, invasion, and tumor growth. Conversely, CK2 depletion or treatment with a CK2 inhibitor reversed these effects. Our findings reveal a novel mechanism by which the CK2/PD-L1/EGFR pathway promotes tumor progression.
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Affiliation(s)
- Suning Che
- School of Life Science, Jiangsu University, Zhenjiang, Jiangsu Province, 212013, China
| | - Yao Zhang
- School of Life Science, Jiangsu University, Zhenjiang, Jiangsu Province, 212013, China
| | - Huihui Xu
- School of Life Science, Jiangsu University, Zhenjiang, Jiangsu Province, 212013, China
| | - Juanjuan Shi
- School of Life Science, Jiangsu University, Zhenjiang, Jiangsu Province, 212013, China
| | - Yongzhong Hou
- School of Life Science, Jiangsu University, Zhenjiang, Jiangsu Province, 212013, China.
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Liu J, Wu Z, Zhou S, Lv W, Wang Y, Xia P, Zhu L, Hu J. Neoadjuvant immunochemotherapy for locally advanced esophageal squamous cell carcinoma in real-world practice: an analysis of the clinical outcomes and long-term survival, and the feasibility of using major pathological response as a surrogate endpoint. Eur J Med Res 2025; 30:342. [PMID: 40301916 PMCID: PMC12038973 DOI: 10.1186/s40001-025-02599-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2024] [Accepted: 04/15/2025] [Indexed: 05/01/2025] Open
Abstract
BACKGROUND Neoadjuvant immunochemotherapy is expected to become the standard treatment mode for locally advanced esophageal squamous cell carcinoma (ESCC). This study aims to analyze the clinical outcomes and long-term survival of neoadjuvant immunochemotherapy for locally advanced ESCC, and explore the feasibility of using major pathological response (MPR) as a surrogate endpoint. METHODS This real-world retrospective study consecutively included eligible patients with stage II-IVA locally advanced ESCC who received neoadjuvant immunochemotherapy and surgery between 2019 and 2022 at the Department of Thoracic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine. RESULTS This study collected a total of 166 patients, and ultimately included 126 patients after screening. The objective response rate (ORR) was 69.8% (88/126). The incidence of grade 3-4 adverse events (AEs) was 13.5% (17/126). MPR was observed in 49 (38.9%) patients, and 24 (19.0%) patients achieved a complete pathological response (pCR). The median progression-free survival (PFS) was 31.7 months and the 3-year PFS rate was 56.3%. The median overall survival (OS) was not reached and the 3-year OS rate was 70.6%. The median PFS of the non-MPR group was 25.0 months, with the MPR group not achieved (hazard ratio [HR], 2.503; 95% CI 1.359-4.610; P = 0.0022). The median OS in the non-MPR group was 31.7 months and not reached in the MPR group (HR, 3.607; 95% CI 1.576-8.254; P = 0.0012). MPR is an independent prognostic factor affecting OS (HR, 2.522; 95% CI 1.018-6.401; P = 0.046). CONCLUSIONS Neoadjuvant immunochemotherapy is safe and effective for locally advanced ESCC, and can result in certain survival benefits. MPR can serve as a surrogate endpoint for predicting long-term OS.
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Affiliation(s)
- Jiacong Liu
- Department of Thoracic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, No. 79 Qingchun Road, Hangzhou, 310003, China
| | - Ziheng Wu
- Department of Thoracic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
| | - Shihong Zhou
- Department of Thoracic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, No. 79 Qingchun Road, Hangzhou, 310003, China
| | - Wang Lv
- Department of Thoracic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, No. 79 Qingchun Road, Hangzhou, 310003, China
| | - Yiqing Wang
- Department of Thoracic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, No. 79 Qingchun Road, Hangzhou, 310003, China
| | - Pinghui Xia
- Department of Thoracic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, No. 79 Qingchun Road, Hangzhou, 310003, China
| | - Linhai Zhu
- Department of Thoracic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, No. 79 Qingchun Road, Hangzhou, 310003, China.
| | - Jian Hu
- Department of Thoracic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, No. 79 Qingchun Road, Hangzhou, 310003, China.
- Key Laboratory of Clinical Evaluation Technology for Medical Device of Zhejiang Province, Hangzhou, 310003, China.
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Wang X, Cheng M, Chen S, Zhang C, Ling R, Qiu S, Chen K, Zhou B, Li Q, Lei W, Chen D. Resistance to anti-LAG-3 plus anti-PD-1 therapy in head and neck cancer is mediated by Sox9+ tumor cells interaction with Fpr1+ neutrophils. Nat Commun 2025; 16:3975. [PMID: 40295483 PMCID: PMC12037843 DOI: 10.1038/s41467-025-59050-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2024] [Accepted: 04/07/2025] [Indexed: 04/30/2025] Open
Abstract
Relatlimab and nivolumab combination therapy shows significant efficacy in treating various types of cancer. Current research on the molecular mechanisms of this treatment is abundant, but in-depth investigations into post-treatment resistance remain notably lacking. In this study, we identify significant enrichment of SRY (sex determining region Y)-box 9 (Sox9)+ tumor cells in resistant samples using single cell RNA sequencing (scRNAseq) in a head and neck squamous cell carcinoma (HNSCC) mouse model. In addition, Sox9 directly regulates the expression of annexin A1 (Anxa1), mediating apoptosis of formyl peptide receptor 1 (Fpr1)+ neutrophils through the Anxa1-Fpr1 axis, which promotes mitochondrial fission, inhibits mitophagy by downregulating BCL2/adenovirus E1B interacting protein 3 (Bnip3) expression and ultimately prevents the accumulation of neutrophils in tumor tissues. The reduction of Fpr1+ neutrophils impairs the infiltration and tumor cell-killing ability of cytotoxic Cd8 T and γδT cells within the tumor microenvironment, thereby leading to the development of resistance to the combination therapy. We further validate these findings using various transgenic mouse models. Overall, this study comprehensively explains the mechanisms underlying resistance to the anti-LAG-3 plus anti-PD-1 combination therapy and identifies potential therapeutic targets to overcome this resistance.
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Affiliation(s)
- Xiaochen Wang
- Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Maosheng Cheng
- Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Shuang Chen
- Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Caihua Zhang
- Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Rongsong Ling
- Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Shuqing Qiu
- Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Ke Chen
- Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Bin Zhou
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.
| | - Qiuli Li
- Department of Head and Neck Surgery, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China.
| | - Wenbin Lei
- Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.
| | - Demeng Chen
- Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.
- State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, China.
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Chiu DKC, Zhang X, Cheng BYL, Liu Q, Hayashi K, Yu B, Lee R, Zhang C, An X, Rajadas J, Reticker-Flynn NE, Rankin EB, Engleman EG. Tumor-derived erythropoietin acts as an immunosuppressive switch in cancer immunity. Science 2025; 388:eadr3026. [PMID: 40273234 PMCID: PMC12110762 DOI: 10.1126/science.adr3026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2024] [Revised: 12/20/2024] [Accepted: 03/05/2025] [Indexed: 04/26/2025]
Abstract
Successful cancer immunotherapy requires a patient to mount an effective immune response against tumors; however, many cancers evade the body's immune system. To investigate the basis for treatment failure, we examined spontaneous mouse models of hepatocellular carcinoma (HCC) with either an inflamed T cell-rich or a noninflamed T cell-deprived tumor microenvironment (TME). Our studies reveal that erythropoietin (EPO) secreted by tumor cells determines tumor immunotype. Tumor-derived EPO autonomously generates a noninflamed TME by interacting with its cognate receptor EPOR on tumor-associated macrophages (TAMs). EPO signaling prompts TAMs to become immunoregulatory through NRF2-mediated heme depletion. Removing either tumor-derived EPO or EPOR on TAMs leads to an inflamed TME and tumor regression independent of genotype, owing to augmented antitumor T cell immunity. Thus, the EPO/EPOR axis functions as an immunosuppressive switch for antitumor immunity.
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Affiliation(s)
| | - Xiangyue Zhang
- Department of Pathology, Stanford University, Stanford, CA 94305, USA
| | | | - Qiang Liu
- Biomaterials and Advanced Drug Delivery Laboratory, Stanford University School of Medicine, Stanford, CA, USA
| | - Kazukuni Hayashi
- Department of Pathology, Stanford University, Stanford, CA 94305, USA
| | - Bo Yu
- ImmunEdge Inc. Mountain View, California 94043, USA
| | - Ryan Lee
- Department of Pathology, Stanford University, Stanford, CA 94305, USA
| | - Catherine Zhang
- Department of Pathology, Stanford University, Stanford, CA 94305, USA
| | - Xiuli An
- Laboratory of Membrane Biology, New York Blood Center, New York, NY, 10065, USA
| | - Jayakumar Rajadas
- Biomaterials and Advanced Drug Delivery Laboratory, Stanford University School of Medicine, Stanford, CA, USA
| | - Nathan E Reticker-Flynn
- Department of Otolaryngology - Head and Neck Surgery, Stanford University, Stanford, CA 94305, USA
| | - Erinn B Rankin
- Department of Radiation Oncology, Stanford University, Stanford, CA 94305, USA
- Stanford Cancer Institute, Stanford University, Palo Alto, CA 94305, USA
| | - Edgar G Engleman
- Department of Pathology, Stanford University, Stanford, CA 94305, USA
- Stanford Cancer Institute, Stanford University, Palo Alto, CA 94305, USA
- Lead contact
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Zhang Z, Zhao H, Wang P, Geng X, Yin M, Liu Y, Zhang S, Liang Y, Ji J, Zheng G. A Novel Prognostic Signature Integrating Immune and Glycolytic Pathways for Enhanced Prognosis and Immunotherapy Prediction in Hepatocellular Carcinoma. J Hepatocell Carcinoma 2025; 12:805-823. [PMID: 40264860 PMCID: PMC12013648 DOI: 10.2147/jhc.s510460] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2024] [Accepted: 04/10/2025] [Indexed: 04/24/2025] Open
Abstract
Background This study aimed to establish an immune-glycolysis-related prognostic signature (IGRPS) to predict hepatocellular carcinoma (HCC) outcomes. Additionally, it explored the role of this signature in the tumor immune microenvironment (TIME), glycolytic pathways, and immunotherapy. Methods We analyzed RNA-seq, single-cell sequencing, and immune- and glycolysis-related gene datasets from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). Using weighted gene co-expression network analysis (WGCNA), F-test, and Cox regression, we identified key survival-related immune and glycolytic genes (SRIGRGs) and developed an IGRPS through multivariate Cox regression. The IGRPS's predictive performance was validated in training and validation cohorts using Kaplan-Meier survival analysis, receiver operating characteristic (ROC) curves, and a prognostic nomogram. Its correlation with TIME and its ability to predict immunotherapy outcomes were also assessed. In vitro experiments were conducted to analyze the expression and function of IGRPS genes in HCC. Results Thirteen SRIGRGs were identified for constructing the IGRPS. Patients with low-risk scores had significantly longer survival times. The area under the curve (AUC) for ROC curves was over 0.73 for training and 0.7 for validation cohorts, with C-indices of 0.721 and 0.79, respectively. IGRPS was confirmed as an independent prognostic indicator. Patients in the low-risk group showed better responses to combined anti-CTLA4 and anti-PD-1 therapies. In vitro experiments indicated that PRKAG1 and B3GAT3 were upregulated, enhancing glycolysis and promoting HCC cell proliferation and migration. Conclusion The IGRPS, based on immune- and glycolysis-related genes, effectively predicted prognosis and immunotherapy responses in HCC patients.
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Affiliation(s)
- Zeyu Zhang
- Department of Clinical Laboratory, Qilu Hospital of Shandong University, Jinan, Shandong, 250012, People’s Republic of China
| | - Hongxi Zhao
- Department of Clinical Laboratory, Qilu Hospital of Shandong University, Jinan, Shandong, 250012, People’s Republic of China
| | - Pengyu Wang
- Faculty of Science, University of Alberta, Edmonton, Alberta, T6G 2E9, Canada
| | - Xueyan Geng
- Department of Clinical Laboratory, Qilu Hospital of Shandong University, Jinan, Shandong, 250012, People’s Republic of China
| | - Maopeng Yin
- Department of Clinical Laboratory, Qilu Hospital of Shandong University, Jinan, Shandong, 250012, People’s Republic of China
| | - Yingjie Liu
- Department of Clinical Laboratory, Qilu Hospital of Shandong University, Jinan, Shandong, 250012, People’s Republic of China
| | - Shoucai Zhang
- Department of Clinical Laboratory, Qilu Hospital of Shandong University, Jinan, Shandong, 250012, People’s Republic of China
| | - Yongyuan Liang
- Department of Clinical Laboratory, Qilu Hospital of Shandong University, Jinan, Shandong, 250012, People’s Republic of China
| | - Jian Ji
- Department of Clinical Laboratory, Qilu Hospital of Shandong University, Jinan, Shandong, 250012, People’s Republic of China
| | - Guixi Zheng
- Department of Clinical Laboratory, Qilu Hospital of Shandong University, Jinan, Shandong, 250012, People’s Republic of China
- Shandong Engineering Research Center of Biomarker and Artificial Intelligence Application, Jinan, Shandong, 250012, People’s Republic of China
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Li X, Pan L, Li W, Liu B, Xiao C, Chew V, Zhang X, Long W, Ginhoux F, Loscalzo J, Buggert M, Zhang X, Sheng R, Wang Z. Deciphering immune predictors of immunotherapy response: A multiomics approach at the pan-cancer level. Cell Rep Med 2025; 6:101992. [PMID: 40054456 PMCID: PMC12047473 DOI: 10.1016/j.xcrm.2025.101992] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2024] [Revised: 01/15/2025] [Accepted: 02/05/2025] [Indexed: 04/18/2025]
Abstract
Immune checkpoint blockade (ICB) therapy has transformed cancer treatment, yet many patients fail to respond. Employing single-cell multiomics, we unveil T cell dynamics influencing ICB response across 480 pan-cancer and 27 normal tissue samples. We identify four immunotherapy response-associated T cells (IRATs) linked to responsiveness or resistance and analyze their pseudotemporal patterns, regulatory mechanisms, and T cell receptor clonal expansion profiles specific to each response. Notably, transforming growth factor β1 (TGF-β1)+ CD4+ and Temra CD8+ T cells negatively correlate with therapy response, in stark contrast to the positive response associated with CXCL13+ CD4+ and CD8+ T cells. Validation with a cohort of 23 colorectal cancer (CRC) samples confirms the significant impact of TGF-β1+ CD4+ and CXCL13+ CD4+ and CD8+ T cells on ICB efficacy. Our study highlights the effectiveness of single-cell multiomics in pinpointing immune markers predictive of immunotherapy outcomes, providing an important resource for crafting targeted immunotherapies for successful ICB treatment across cancers.
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Affiliation(s)
- Xuexin Li
- Department of General Surgery, The Fourth Affiliated Hospital, China Medical University, Shenyang, Liaoning 110032, China; Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, Shenyang, Liaoning 110122, China; Institute of Health Sciences, China Medical University, Shenyang, Liaoning 110122, China; Department of Physiology and Pharmacology, Karolinska Institutet, 171 65 Solna, Sweden.
| | - Lu Pan
- Institute of Environmental Medicine, Karolinska Institutet, 171 65 Solna, Sweden
| | - Weiyuan Li
- School of Medicine, Yunnan University, Kunming, Yunnan 650091, China; Department of Reproductive Medicine, The First People's Hospital of Yunnan Province, Kunming, Yunnan 650021, China
| | - Bingyang Liu
- Department of Endocrinology, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, China
| | - Chunjie Xiao
- School of Medicine, Yunnan University, Kunming, Yunnan 650091, China
| | - Valerie Chew
- Translational Immunology Institute (TII), SingHealth-Duke NUS Academic Medical Centre, Singapore 169856, Singapore
| | - Xuan Zhang
- Department of Colorectal Surgery, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, China
| | - Wang Long
- Department of Pathology, Nihon University, Tokyo 102-0074, Japan
| | - Florent Ginhoux
- Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A∗STAR), Singapore 138648, Singapore; Institut Gustave Roussy, INSERM U1015, Bâtiment de Médecine Moléculaire 114 rue Edouard Vaillant, 94800 Villejuif, France; Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Joseph Loscalzo
- Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Marcus Buggert
- Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, 141 52 Huddinge, Sweden
| | - Xiaolu Zhang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China; Shenzhen Research Institute of Shandong University, Shenzhen, Guangdong 518057, China.
| | - Ren Sheng
- College of Life and Health Sciences, Northeastern University, Shenyang, Liaoning 110819, China; School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, Guangdong 510000, China.
| | - Zhenning Wang
- Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, Shenyang, Liaoning 110122, China; Institute of Health Sciences, China Medical University, Shenyang, Liaoning 110122, China; The First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110001, China.
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41
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Liao S, Sun H, Lu H, Wu J, Wu J, Wu Z, Xi J, Liao W, Wang Y. Neutrophil-to-lymphocyte ratio-based prognostic score can predict outcomes in patients with advanced non-small cell lung cancer treated with immunotherapy plus chemotherapy. BMC Cancer 2025; 25:697. [PMID: 40234811 PMCID: PMC11998248 DOI: 10.1186/s12885-025-13811-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2024] [Accepted: 02/25/2025] [Indexed: 04/17/2025] Open
Abstract
BACKGROUD Immune checkpoint inhibitor (ICI) plus chemotherapy has become the standard of care for advanced non-small cell lung cancer (NSCLC). Nonetheless, reliable efficacy biomarkers of ICI plus chemotherapy are lacking. In this research, we sought to explore efficacy biomarkers and construct robust prognostic models in NSCLC patients treated with ICI plus chemotherapy. METHODS We retrospectively analyzed 171 patients with advanced NSCLC treated with ICI plus chemotherapy. Clinical characteristics and peripheral blood inflammatory indexes were collected and prognostic models were constructed to explore efficacy and prognosis biomarkers of ICI plus chemotherapy. RESULTS In the cohort that received first-line ICI plus chemotherapy, pre-treatment neutrophil-to-lymphocyte ratio (NLR) > 3.3 and fibrinogen (FIB) > 3.196 were associated with worse efficacy and were independent risk factors of progression-free survival (PFS). Compared to programmed cell death ligand 1 (PD-L1), the derived NLR-FIB (NF) score had significantly improved accuracy in predicting efficacy and prognosis. In advanced NSCLC patients with targetable oncogenic driver alterations receiving second- or post-line ICI plus chemotherapy, pre-treatment NLR > 3.53 was associated with worse efficacy and was an independent risk factor of PFS and OS; Tyrosine kinase inhibitor (TKI)-PFS > 12 months were independent risk factors of overall survival (OS). Secondary epidermal growth factor receptor (EGFR)-T790M mutation, platelet-to-lymphocyte ratio (PLR) > 196.81 and albumin (ALB) < 40.25 were associated with worse PFS. Based on NLR and TKI-PFS, an NLR-TKI-PFS (NTP) score was constructed with three OS risk prognosis categories: favorable, intermediate, and poor (corresponding to a median OS of 21, 12, and 5.3 months). CONCLUSIONS The noninvasive NF score, combining NLR > 3.3 and FIB > 3.196, was superior to PD-L1 estimated from tumor tissue in predicting the efficacy and prognosis of first-line ICI plus chemotherapy in advanced NSCLC patients. The noninvasive NTP score, combining NLR > 3.53 and TKI-PFS > 12 months, is a valuable tool for predicting OS and PFS in advanced NSCLC patients with targetable oncogenic driver alterations receiving second- or post-line ICI combination therapy.
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Affiliation(s)
- Shan Liao
- Department of Oncology, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Avenue, Guangzhou, 510515, Guangdong, China
| | - Huiying Sun
- Department of Oncology, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Avenue, Guangzhou, 510515, Guangdong, China
| | - Hao Lu
- Department of Oncology, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Avenue, Guangzhou, 510515, Guangdong, China
| | - Jiani Wu
- Department of Oncology, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Avenue, Guangzhou, 510515, Guangdong, China
| | - Jianhua Wu
- Department of Oncology, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Avenue, Guangzhou, 510515, Guangdong, China
| | - Zhe Wu
- Department of Oncology, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Avenue, Guangzhou, 510515, Guangdong, China
| | - Jingle Xi
- Department of Oncology, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Avenue, Guangzhou, 510515, Guangdong, China
| | - Wangjun Liao
- Department of Oncology, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Avenue, Guangzhou, 510515, Guangdong, China.
- Cancer Center, the Sixth Affiliated Hospital, School of Medicine, South China University of Technology, Foshan, China.
| | - Yuanyuan Wang
- Department of Oncology, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Avenue, Guangzhou, 510515, Guangdong, China.
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42
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Wang SL, Chan TA. Navigating established and emerging biomarkers for immune checkpoint inhibitor therapy. Cancer Cell 2025; 43:641-664. [PMID: 40154483 DOI: 10.1016/j.ccell.2025.03.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2025] [Revised: 02/19/2025] [Accepted: 03/04/2025] [Indexed: 04/01/2025]
Abstract
Immune checkpoint inhibitors (ICIs) have improved outcomes of patients with many different cancers. These antibodies target molecules such as programmed cell death 1 (PD-1) or cytotoxic T lymphocyte associated protein 4 (CTLA-4) which normally function to limit immune activity. Treatment with ICIs reactivates T cells to destroy tumor cells in a highly specific manner, which in some patients, results in dramatic remissions and durable disease control. Over the last decade, much effort has been directed at characterizing factors that drive efficacy and resistance to ICI therapy. Food and Drug Administration (FDA)-approved biomarkers for ICI therapy have facilitated more judicious treatment of cancer patients and transformed the field of precision oncology. Yet, adaptive immunity against cancers is complex, and newer data have revealed the potential utility of other biomarkers. In this review, we discuss the utility of currently approved biomarkers and highlight how emerging biomarkers can further improve the identification of patients who benefit from ICIs.
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Affiliation(s)
- Stephen L Wang
- Center for Immunotherapy and Precision Immuno-Oncology, Cleveland Clinic, Cleveland, OH, USA; Medical Scientist Training Program, Case Western Reserve University School of Medicine, Cleveland, OH, USA; Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH, USA
| | - Timothy A Chan
- Center for Immunotherapy and Precision Immuno-Oncology, Cleveland Clinic, Cleveland, OH, USA; National Center for Regenerative Medicine, Cleveland, OH, USA.
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43
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Oh H, Jang I, Hwang J, Lee S, An J, Sim J. Clinicopathologic Analysis of Five Patients with POLE-Mutated Colorectal Cancer in a Single Korean Institute. Diagnostics (Basel) 2025; 15:972. [PMID: 40310397 PMCID: PMC12025746 DOI: 10.3390/diagnostics15080972] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2025] [Revised: 04/06/2025] [Accepted: 04/08/2025] [Indexed: 05/02/2025] Open
Abstract
Background/Objectives: Mutations in RAS/RAF are common in colorectal cancer (CRC) and play a pivotal role in guiding treatment selection. With the recent advent of immunotherapy, microsatellite (MSI) status, tumor mutation burden (TMB), and POLE mutations, particularly those leading to high TMB, have gained importance in CRC. This study aimed to examine the clinicopathological characteristics of patients with CRC with POLE mutations. Methods: We identified POLE mutations in patients with colorectal cancer who had available next-generation sequencing (NGS) results from a single institute in Korea. RAS/RAF status, MSI status, and TMB were evaluated, and based on the TMB results, patients with POLE mutations were classified as having either pathogenic or non-pathogenic mutations. After excluding non-Korean patients, we compared the groups based on the presence of pathogenic POLE mutations. Results: Five POLE mutations (A456P, P286R, R1111W, R609W, and V922I) were identified. Only A456P and P286R were associated with an exceptionally high TMB, resulting in two patients (1.1%) being categorized as having pathogenic POLE. The POLE-mutant group showed an extremely high TMB and tended to include younger patients. Among the two pathogenic cases, one showed poor histological differentiation, and the tumors were split between the right and left colons (one in each). Conclusions: CRC with POLE mutations tend to exhibit TMB-high, occur in younger patients, localize to the right colon, and display poor histological differentiation. Given that POLE mutations can serve as indicators for immunotherapy, recognizing these mutations is of clinical importance.
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Affiliation(s)
- Harim Oh
- Department of Pathology, Korea University Anam Hospital, Korea University College of Medicine, 73 Anam-ro, Seongbuk-gu, Seoul 02841, Republic of Korea;
| | - Inho Jang
- Department of Medicine, Korea University College of Medicine, Seoul 02841, Republic of Korea;
| | - Jinha Hwang
- Department of Laboratory Medicine, Korea University Anam Hospital, Korea University College of Medicine, Seoul 02841, Republic of Korea;
| | - Soohyeon Lee
- Division of Medical Oncology, Department of Internal Medicine, Korea University Anam Hospital, Korea University College of Medicine, Seoul 02841, Republic of Korea;
| | - Jungsuk An
- Department of Pathology, Ewha Womans University Mokdong Hospital, Ewha Womans University College of Medicine, Seoul 07985, Republic of Korea;
| | - Jongmin Sim
- Department of Pathology, Korea University Anam Hospital, Korea University College of Medicine, 73 Anam-ro, Seongbuk-gu, Seoul 02841, Republic of Korea;
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44
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Oka T, Smith SS, Oliver-Garcia VS, Lee T, Son HG, Mortaja M, Azin M, Garza-Mayers AC, Huang JT, Nazarian RM, Horn TD, Demehri S. Epigenomic regulation of stemness contributes to the low immunogenicity of the most mutated human cancer. Cell Rep 2025:115561. [PMID: 40250424 DOI: 10.1016/j.celrep.2025.115561] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2024] [Revised: 12/02/2024] [Accepted: 03/24/2025] [Indexed: 04/20/2025] Open
Abstract
Despite harboring the highest tumor mutational burden of all cancers, basal cell carcinoma (BCC) has low immunogenicity. Here, we demonstrate that BCC's low immunogenicity is associated with epigenomic suppression of antigen presentation machinery reminiscent of its cell of origin. Primary BCC had low T cell infiltrates and low human leukocyte antigen class I (HLA-I) expression compared with cutaneous squamous cell carcinoma (SCC) and normal keratinocytes. Forkhead box C1 (Foxc1), a regulator of quiescence in hair follicle stem cells, was expressed in BCC. Foxc1 bound to promoter of interferon regulatory factor 1 and HLA-I genes, leading to their deacetylation and reduced expression. A histone deacetylase inhibitor, entinostat, overcame Foxc1's effect and upregulated HLA-I in BCC. Topical entinostat plus imiquimod immunotherapy blocked BCC development in mice. Collectively, our findings demonstrate that low BCC immunogenicity is associated with a stem-like quiescent program preserved in the tumor cells, which can be blocked to enable BCC immunotherapy.
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Affiliation(s)
- Tomonori Oka
- Center for Cancer Immunology and Cutaneous Biology Research Center, Department of Dermatology and Krantz Family Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Sabrina S Smith
- Center for Cancer Immunology and Cutaneous Biology Research Center, Department of Dermatology and Krantz Family Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Valeria S Oliver-Garcia
- Center for Cancer Immunology and Cutaneous Biology Research Center, Department of Dermatology and Krantz Family Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Truelian Lee
- Center for Cancer Immunology and Cutaneous Biology Research Center, Department of Dermatology and Krantz Family Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Heehwa G Son
- Center for Cancer Immunology and Cutaneous Biology Research Center, Department of Dermatology and Krantz Family Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Mahsa Mortaja
- Center for Cancer Immunology and Cutaneous Biology Research Center, Department of Dermatology and Krantz Family Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Marjan Azin
- Center for Cancer Immunology and Cutaneous Biology Research Center, Department of Dermatology and Krantz Family Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Anna C Garza-Mayers
- Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Jennifer T Huang
- Dermatology Section, Division of Immunology, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA
| | - Rosalynn M Nazarian
- Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Thomas D Horn
- Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Shadmehr Demehri
- Center for Cancer Immunology and Cutaneous Biology Research Center, Department of Dermatology and Krantz Family Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
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45
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Jiang Q, Braun DA, Clauser KR, Ramesh V, Shirole NH, Duke-Cohan JE, Nabilsi N, Kramer NJ, Forman C, Lippincott IE, Klaeger S, Phulphagar KM, Chea V, Kim N, Vanasse AP, Saad E, Parsons T, Carr-Reynolds M, Carulli I, Pinjusic K, Jiang Y, Li R, Syamala S, Rachimi S, Verzani EK, Stevens JD, Lane WJ, Camp SY, Meli K, Pappalardi MB, Herbert ZT, Qiu X, Cejas P, Long HW, Shukla SA, Van Allen EM, Choueiri TK, Churchman LS, Abelin JG, Gurer C, MacBeath G, Childs RW, Carr SA, Keskin DB, Wu CJ, Kaelin WG. HIF regulates multiple translated endogenous retroviruses: Implications for cancer immunotherapy. Cell 2025; 188:1807-1827.e34. [PMID: 40023154 PMCID: PMC11988688 DOI: 10.1016/j.cell.2025.01.046] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2024] [Revised: 11/14/2024] [Accepted: 01/31/2025] [Indexed: 03/04/2025]
Abstract
Clear cell renal cell carcinoma (ccRCC), despite having a low mutational burden, is considered immunogenic because it occasionally undergoes spontaneous regressions and often responds to immunotherapies. The signature lesion in ccRCC is inactivation of the VHL tumor suppressor gene and consequent upregulation of the HIF transcription factor. An earlier case report described a ccRCC patient who was cured by an allogeneic stem cell transplant and later found to have donor-derived T cells that recognized a ccRCC-specific peptide encoded by a HIF-responsive endogenous retrovirus (ERV), ERVE-4. We report that ERVE-4 is one of many ERVs that are induced by HIF, translated into HLA-bound peptides in ccRCCs, and capable of generating antigen-specific T cell responses. Moreover, ERV expression can be induced in non-ccRCC tumors with clinical-grade HIF stabilizers. These findings have implications for leveraging ERVs for cancer immunotherapy.
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Affiliation(s)
- Qinqin Jiang
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA
| | - David A Braun
- Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; Yale Center of Cellular and Molecular Oncology, Yale School of Medicine, New Haven, CT 06511, USA
| | - Karl R Clauser
- Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA
| | - Vijyendra Ramesh
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA
| | - Nitin H Shirole
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA
| | - Joseph E Duke-Cohan
- Translational Immunogenomics Laboratory, Dana-Farber Cancer Institute, Boston, MA 02215, USA
| | | | - Nicholas J Kramer
- Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA 02215, USA
| | - Cleo Forman
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA
| | - Isabelle E Lippincott
- Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA
| | - Susan Klaeger
- Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA
| | - Kshiti M Phulphagar
- Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA
| | - Vipheaviny Chea
- Translational Immunogenomics Laboratory, Dana-Farber Cancer Institute, Boston, MA 02215, USA
| | - Nawoo Kim
- Translational Immunogenomics Laboratory, Dana-Farber Cancer Institute, Boston, MA 02215, USA
| | - Allison P Vanasse
- Translational Immunogenomics Laboratory, Dana-Farber Cancer Institute, Boston, MA 02215, USA
| | - Eddy Saad
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA
| | | | | | - Isabel Carulli
- Translational Immunogenomics Laboratory, Dana-Farber Cancer Institute, Boston, MA 02215, USA
| | - Katarina Pinjusic
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; Translational Immunogenomics Laboratory, Dana-Farber Cancer Institute, Boston, MA 02215, USA
| | - Yijia Jiang
- Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA
| | - Rong Li
- Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA
| | - Sudeepa Syamala
- Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA
| | - Suzanna Rachimi
- Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA
| | - Eva K Verzani
- Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA
| | - Jonathan D Stevens
- Department of Pathology, Brigham and Women's Hospital, Boston, MA 02215, USA
| | - William J Lane
- Department of Pathology, Brigham and Women's Hospital, Boston, MA 02215, USA
| | - Sabrina Y Camp
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA
| | - Kevin Meli
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA
| | | | - Zachary T Herbert
- Molecular Biology Core Facilities, Dana-Farber Cancer Institute, Boston, MA 02215, USA
| | - Xintao Qiu
- Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA
| | - Paloma Cejas
- Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA
| | - Henry W Long
- Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA
| | - Sachet A Shukla
- Department of Hematopoietic Biology and Malignancy, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Eliezer M Van Allen
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA
| | - Toni K Choueiri
- Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02215, USA
| | - L Stirling Churchman
- Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA 02215, USA
| | - Jennifer G Abelin
- Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA
| | | | | | - Richard W Childs
- Laboratory of Transplantation Immunotherapy, Cellular and Molecular Therapeutics Branch, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Steven A Carr
- Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA.
| | - Derin B Keskin
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA; Translational Immunogenomics Laboratory, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Computer Science, Metropolitan College, Boston University, Boston, MA 02215, USA; Section for Bioinformatics, Department of Health Technology, Technical University of Denmark 2800 Lyngby, Denmark.
| | - Catherine J Wu
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02215, USA.
| | - William G Kaelin
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02215, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.
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Oyama K, Nakata K, Abe T, Hirotaka K, Fujimori N, Kiyotani K, Iwamoto C, Ikenaga N, Morisaki S, Umebayashi M, Tanaka H, Koya N, Nakagawa S, Tsujimura K, Yoshimura S, Onishi H, Nakamura Y, Nakamura M, Morisaki T. Neoantigen peptide-pulsed dendritic cell vaccine therapy after surgical treatment of pancreatic cancer: a retrospective study. Front Immunol 2025; 16:1571182. [PMID: 40248703 PMCID: PMC12004129 DOI: 10.3389/fimmu.2025.1571182] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2025] [Accepted: 03/10/2025] [Indexed: 04/19/2025] Open
Abstract
Introduction Pancreatic cancer shows very poor prognosis and high resistance to conventional standard chemotherapy and immunotherapy; therefore, the development of new breakthrough therapies is highly desirable. Method We retrospectively evaluated the safety and efficacy of neoantigen peptide-pulsed dendritic cell (Neo-P DC) vaccine therapy after surgical treatment of pancreatic cancer. Result The result showed induction of neoantigen-specific T cells in 13 (81.3%) of the 16 patients who received Neo-P DC vaccines. In survival analysis of the nine patients who received Neo-P DC vaccines after recurrence, longer overall survival was observed in patients with neoantigen-specific T cell induction than those without T cell induction. Notably, only one of the seven patients who received Neo-P DC vaccines as adjuvant setting developed recurrence, and no patient died during median follow-up 61 months after surgery (range, 25-70 months). Furthermore, TCR repertoire analyses were performed in a case treated with Neo-P DC vaccine combined with long and short peptides, and one significantly dominant clone induced by the long peptide was detected among CD4+ T cell populations. Discussion The present study suggests the feasibility and efficacy of Neo-P DC vaccine therapy after surgical treatment of pancreatic cancer in both postoperative recurrence cases and adjuvant setting. A case analysis suggests the importance of combination with long peptides targeting CD4+ T cell.
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Affiliation(s)
- Koki Oyama
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Kohei Nakata
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Toshiya Abe
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Kento Hirotaka
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Nao Fujimori
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Kazuma Kiyotani
- Laboratory of Immunogenomics, Center for Intractable Diseases and ImmunoGenomics, National Institute of Biomedical Innovation, Health and Nutrition, Osaka, Japan
| | - Chika Iwamoto
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Naoki Ikenaga
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Shinji Morisaki
- Department of Cancer Immunotherapy, Fukuoka General Cancer Clinic, Fukuoka, Japan
- Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Masayo Umebayashi
- Department of Cancer Immunotherapy, Fukuoka General Cancer Clinic, Fukuoka, Japan
| | - Hiroto Tanaka
- Department of Cancer Immunotherapy, Fukuoka General Cancer Clinic, Fukuoka, Japan
| | - Norihiro Koya
- Department of Cancer Immunotherapy, Fukuoka General Cancer Clinic, Fukuoka, Japan
| | - Shinichiro Nakagawa
- Department of Cancer Immunotherapy, Fukuoka General Cancer Clinic, Fukuoka, Japan
| | - Kenta Tsujimura
- Department of Cancer Immunotherapy, Fukuoka General Cancer Clinic, Fukuoka, Japan
| | - Sachiko Yoshimura
- Corporate Headquarters, Cancer Precision Medicine Inc., Kawasaki, Japan
| | - Hideya Onishi
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yusuke Nakamura
- Laboratory of Immunogenomics, Center for Intractable Diseases and ImmunoGenomics, National Institute of Biomedical Innovation, Health and Nutrition, Osaka, Japan
| | - Masafumi Nakamura
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Takashi Morisaki
- Department of Cancer Immunotherapy, Fukuoka General Cancer Clinic, Fukuoka, Japan
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47
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Xiong Z, Sneiderman CT, Kuminkoski CR, Reinheimer J, Schwegman L, Sever RE, Habib A, Hu B, Agnihotri S, Rajasundaram D, Zinn PO, Forsthuber TG, Pollack IF, Li X, Raphael I, Kohanbash G. Transcript-targeted antigen mapping reveals the potential of POSTN splicing junction epitopes in glioblastoma immunotherapy. Genes Immun 2025:10.1038/s41435-025-00326-6. [PMID: 40181162 DOI: 10.1038/s41435-025-00326-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2024] [Revised: 03/13/2025] [Accepted: 03/21/2025] [Indexed: 04/05/2025]
Abstract
Tumor antigens are crucial for T-cell mediated immunotherapy, but identified antigens for gliomas remain limited. Aberrant splicing variants are commonly expressed in tumors, resulting in unique tumor isoforms with potential antigenic properties. Herein, we analyzed multi-omics data from 587 glioma patients and assembled a library of putative tumor-enriched isoform antigens (TIA) and corresponding peptides presented on each HLA-I allele. We constructed an individual-specific TIA peptide candidate repertoire for each patient based on their TIA expression and HLA-I haplotypes. TIAs were highly expressed, enriched with glioma malignancy, and demonstrated strong HLA-binding affinity. We focused on periostin isoform-203 (POSTN-203), which was associated with poor survival of patients and contained multiple predicted HLA-restricted peptide epitopes. A selected HLA-A11-restricted peptide from POSTN-203 (POSTN-203A11) induced antigen-specific T-cell responses against both peptide-pulsed and POSTN-203-expressing glioma cells in an HLA-specific manner. Our findings highlight TIAs as a promising source of immunogenic antigens and POSTN-203 as a potential promising target for glioma immunotherapy.
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Affiliation(s)
- Zujian Xiong
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, Hunan, China
- Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, PA, USA
- Xiangya School of Medicine, Central South University, Changsha, Hunan, China
| | - Chaim T Sneiderman
- Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, PA, USA
| | - Chloe R Kuminkoski
- Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, PA, USA
| | - Jared Reinheimer
- Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, PA, USA
| | - Lance Schwegman
- Department of Molecular Microbiology and Immunology, University of Texas at San Antonio, San Antonio, TX, USA
| | - ReidAnn E Sever
- Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, PA, USA
| | - Ahmed Habib
- Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, PA, USA
| | - Baoli Hu
- Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, PA, USA
| | - Sameer Agnihotri
- Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, PA, USA
| | | | - Pascal O Zinn
- Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, PA, USA
| | - Thomas G Forsthuber
- Department of Molecular Microbiology and Immunology, University of Texas at San Antonio, San Antonio, TX, USA
| | - Ian F Pollack
- Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, PA, USA
| | - Xuejun Li
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, Hunan, China
- Hunan International Scientific and Technological Cooperation Base of Brain Tumor Research, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Itay Raphael
- Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, PA, USA
| | - Gary Kohanbash
- Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, PA, USA.
- Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA.
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Zheng L, Nie W, Wang S, Yang L, Hu F, Ma M, Cheng L, Lu J, Zhang B, Xu J, Li Y, Shen Y, Zhang W, Zhong R, Chu T, Han B, Zheng X, Zhong H, Zhang X. Metabolomic machine learning-based model predicts efficacy of chemoimmunotherapy for advanced lung squamous cell carcinoma. Front Immunol 2025; 16:1545976. [PMID: 40242771 PMCID: PMC12000773 DOI: 10.3389/fimmu.2025.1545976] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2024] [Accepted: 03/13/2025] [Indexed: 04/18/2025] Open
Abstract
Background Unlike lung adenocarcinoma, patients with advanced squamous carcinoma exhibit a low proportion of driver gene positivity, with fewer effective treatment strategies available. Chemoimmunotherapy has now become the standard first-line treatment for individuals diagnosed with advanced lung squamous carcinoma. Serum metabolomics holds significant potential for application in predicting responses to chemoimmunotherapy and is capable of identifying and validating potential biomarkers. The aim of our study was to establish a model that can predict the prognosis of chemoimmunotherapy in patients with advanced lung squamous cell carcinoma, integrating metabolomics with machine learning techniques. Methods We collected 79 serum samples from patients with advanced lung squamous cell carcinoma before receiving combined immunotherapy and performed untargeted metabolomics analysis. Patients were divided into non-response (NR) and response (R) groups according to overall survival (OS), and prognostic models were constructed and validated using different machine learning methods. The patients were further categorized into high-risk and low-risk groups based on the median risk score, to assess the model's predictive performance. Results There were significant differences in metabolites and metabolic pathways between NR and R groups, and 117 differential metabolites were preliminarily screened (p < 0.05, VIP > 1). Further, least absolute shrinkage and selection operator (LASSO) and random forest (RF) were used to identify metabolites, and then their common metabolites were used as the best biomarkers to build a prediction model containing 8 differential metabolites. Based on these biomarkers, RF, support vector machine (SVM) and logistic regression were used to randomly divide patients into training and validation sets in a 7:3 ratio, respectively. We found that the RF method resulted in area under curves (AUCs) of 0.973 and 0.944 for the training and validation sets, respectively, with the best predictive performance. Subsequently, both OS and progression-free survival (PFS) were notably reduced in the high-risk group when contrasted with the low-risk group. Conclusions We developed a model containing 8 metabolites based on metabolomics and machine learning that may predict survival outcomes in patients with advanced lung squamous cell carcinoma undergoing chemoimmunotherapy, helping to more accurately assess efficacy and prognosis in clinical practice.
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Affiliation(s)
- Liang Zheng
- Department of Respiratory and Critical Care Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Wei Nie
- Department of Respiratory and Critical Care Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Shuyuan Wang
- Department of Respiratory and Critical Care Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ling Yang
- Department of Ultrasonography, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Fang Hu
- Department of Thoracic Medical Oncology, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Zhejiang, Hangzhou, China
- Hangzhou Institute of Medicine (HlM), Chinese Academy of Sciences, Zhejiang, Hangzhou, China
| | - Meili Ma
- Department of Respiratory and Critical Care Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Lei Cheng
- Department of Respiratory and Critical Care Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jun Lu
- Department of Respiratory and Critical Care Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Bo Zhang
- Department of Respiratory and Critical Care Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jianlin Xu
- Department of Respiratory and Critical Care Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ying Li
- Department of Respiratory and Critical Care Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yinchen Shen
- Department of Respiratory and Critical Care Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Wei Zhang
- Department of Respiratory and Critical Care Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Runbo Zhong
- Department of Respiratory and Critical Care Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Tianqing Chu
- Department of Respiratory and Critical Care Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Baohui Han
- Department of Respiratory and Critical Care Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiaoxuan Zheng
- Department of Respiratory and Critical Care Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Department of Respiratory Endoscopy, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Hua Zhong
- Department of Respiratory and Critical Care Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xueyan Zhang
- Department of Respiratory and Critical Care Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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de Jager VD, Giacomini P, Fairley JA, Toledo RA, Patton SJ, Joosse SA, Koch C, Deans ZC, Pantel K, Heitzer E, Schuuring E. Reporting of molecular test results from cell-free DNA analyses: expert consensus recommendations from the 2023 European Liquid Biopsy Society ctDNA Workshop. EBioMedicine 2025; 114:105636. [PMID: 40121940 PMCID: PMC11979934 DOI: 10.1016/j.ebiom.2025.105636] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2024] [Revised: 02/18/2025] [Accepted: 02/24/2025] [Indexed: 03/25/2025] Open
Abstract
The implementation of circulating tumor DNA (ctDNA) in the diagnostic routine may enable non-invasive predictive biomarker testing and treatment optimization in patients who lack a suitable tumor specimen, have failed previous molecular analysis or are clinically ineligible for (re-)biopsy procedures. As the interpretation and reporting are more complex for ctDNA than conventional tissue-based NGS, there is a need for specific guidelines. These will offer support for the reporting of ctDNA test results and will facilitate optimal communication of liquid biopsy findings between diagnostic laboratories and the medical oncology team. Aiming to generate guidelines based on real-world experiences and broad perspectives, we organized a European Liquid Biopsy Society (ELBS) ctDNA workshop, in which forty-four experts and key stakeholders from different molecular diagnostics laboratories, oncology and pathology departments, as well as an IVDR specialist, convened to address significant challenges associated with the reporting of liquid biopsy test results. This report delineates the resulting consensus recommendations for ctDNA test reporting with underlying rationale and background information.
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Affiliation(s)
- Vincent D de Jager
- Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Patrizio Giacomini
- UOSD Medicina di Precisione in Senologia, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy; Member of the European Liquid Biopsy Society (ELBS) ctDNA Working Group, Hamburg, Germany
| | - Jennifer A Fairley
- GenQA, Department of Laboratory Medicine, NHS Lothian, Nine, Edinburgh Bioquarter, 9 Little France Road, Edinburgh, EH16 4SA, United Kingdom
| | - Rodrigo A Toledo
- Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain
| | - Simon J Patton
- EMQN CIC, Unit 4, Enterprise House, Manchester Science Park, Pencroft Way, Manchester, M15 6SE, United Kingdom
| | - Simon A Joosse
- Department of Tumor Biology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany; Mildred Scheel Cancer Career Center HaTriCS4, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany
| | - Claudia Koch
- Department of Tumor Biology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany; European Liquid Biopsy Society (ELBS), University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246, Hamburg, Germany; Mildred Scheel Cancer Career Center HaTriCS4, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany
| | - Zandra C Deans
- GenQA, Department of Laboratory Medicine, NHS Lothian, Nine, Edinburgh Bioquarter, 9 Little France Road, Edinburgh, EH16 4SA, United Kingdom
| | - Klaus Pantel
- Department of Tumor Biology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany; European Liquid Biopsy Society (ELBS), University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246, Hamburg, Germany; Mildred Scheel Cancer Career Center HaTriCS4, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany
| | - Ellen Heitzer
- Member of the European Liquid Biopsy Society (ELBS) ctDNA Working Group, Hamburg, Germany; Institute of Human Genetics, Diagnostic & Research Center for Molecular BioMedicine, Medical University of Graz, Graz, Austria; Christian Doppler Laboratory for Liquid Biopsies for Early Detection of Cancer, Medical University of Graz, Graz, Austria.
| | - Ed Schuuring
- Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands; Member of the European Liquid Biopsy Society (ELBS) ctDNA Working Group, Hamburg, Germany.
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50
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Li L, Lyu H, Chen Q, Bai Y, Yu J, Cai R. Molecular Characteristics of Prognosis and Chemotherapy Response in Breast Cancer: Biomarker Identification Based on Gene Mutations and Pathway. J Breast Cancer 2025; 28:61-71. [PMID: 40133984 PMCID: PMC12046353 DOI: 10.4048/jbc.2024.0177] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2024] [Revised: 11/18/2024] [Accepted: 12/16/2024] [Indexed: 03/27/2025] Open
Abstract
PURPOSE This study aimed to investigate the molecular characteristics associated with better prognosis in breast cancer. METHODS We performed targeted sequencing of 962 genes in 56 samples, categorizing them into long-term and short-term survival groups as well as chemotherapy-sensitive and chemotherapy-resistant groups for further analyses. RESULTS The results indicated that the tumor mutational burden values were significantly higher in the short-term survival and chemotherapy-resistant groups (p = 0.008 and p = 0.003, respectively). Somatic mutation analysis revealed that the mutation frequencies of BCL9L and WHSC1 were significantly lower in the long-term survival group than those in the short-term survival group (p = 0.029 and p = 0.024, respectively). CREB-regulated transcription coactivator 1 (CRTC1) mutations occurred significantly more frequently in the chemotherapy-resistant group (p = 0.027) and were associated with shorter progression-free survival (p = 0.036). Signature weighting analysis showed a significant increase in Signature.3, which is associated with homologous recombination repair deficiency in the chemotherapy-sensitive group (p = 0.045). Conversely, signatures related to effective DNA repair mechanisms, Signature.1 and Signature.15, were significantly reduced (p = 0.002 and p < 0.001, respectively). Kyoto Encyclopedia of Genes and Genomes pathway analysis indicated that gene mutations were significantly enriched in the JAK-STAT signaling pathway. CONCLUSION This study, through intergroup comparative analysis, found that immunotherapy (using programmed death 1/programmed death-ligand 1 inhibitors) may improve the prognosis of patients with short survival and chemotherapy resistance. Additionally, the study revealed that mutations in BCL9L and WHSC1 could serve as biomarkers for breast cancer prognosis, while CRTC1 mutations and Signature.3 could predict chemotherapy response. The study also found that the JAK-STAT pathway might be a potential therapeutic target for chemotherapy resistance. Therefore, this study identifies molecular characteristics that influence the prognosis of breast cancer patients, providing important theoretical insights for the development of personalized treatment strategies.
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Affiliation(s)
- Liyan Li
- Beijing Pinggu District Maternal and Child Health Care Hospital, Beijing, China
| | - Hongwei Lyu
- Cancer Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | | | | | - Jing Yu
- Cancer Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China.
| | - Ruigang Cai
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
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