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Xu JX, Su YX, Chen YY, Huang YY, Chen ZS, Peng YC, Qi LN. Immune infiltration landscape and potential drug-targeted implications for hepatocellular carcinoma with 'progression/hyper-progression' recurrence. Ann Med 2025; 57:2456113. [PMID: 39865865 PMCID: PMC11774162 DOI: 10.1080/07853890.2025.2456113] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2024] [Revised: 12/20/2024] [Accepted: 01/08/2025] [Indexed: 01/30/2025] Open
Abstract
BACKGROUND AND AIMS Hepatocellular carcinoma (HCC) recurrence was previously characterized into four types, and patients with progression/hyper-progression recurrence (type III-IV) have an extremely poor prognosis. However, the immune background of resectable HCC, particularly in patients who experience recurrence, remains underexplored. Therefore, this study aimed to describe the immune landscape of resectable HCC, especially postoperative type III-IV recurrent HCC, and explore potential immune-targeted anti-relapse strategies for treated populations. METHODS The differences in gene expression in patients with recurrent HCC (type I-II (solitary or multi-intrahepatic oligo recurrence) vs. type III-IV) were investigated using bulk sequencing. Multiple immune infiltration methods (single-sample gene set enrichment analysis (GSEA), Microenvironment Cell Populations-counter and ESTIMATE) were used, and patients were divided into four groups to identify four distinct immune subtypes: immune-enrichment/matrix-poor (IE1), immune-enrichment/matrix-rich (IE2), immune intermediate/matrix-rich (ITM) and immune desert/matrix-poor (ID). Co-expression and protein interaction analyses were used to identify characteristic genes in ITM closely associated with type III-IV recurrence, which was matched with drug targets for Huaier granules (HG) and lenvatinib. Virtual docking was used to identify potential therapeutic targets, and the results were verified using single-nuclei RNA sequencing and histological analysis. RESULTS ITM was closely related to type III-IV recurrence and exhibited immunotherapy potential. The potential efficacy of inhibiting CCNA2, VEGFA, CXCL8, PLK2, TIMP1, ITGB2, ALDOA, ANXA5 and CSK in ITM reversal was determined. Molecular docking demonstrated that the proteins of these genes could bind to HG or lenvatinib. The immunohistochemical findings demonstrated differential VEGFA (p < .01) and PLK2 (p < .001) expression in ITM type and ID in type III-IV recurrent HCC. CONCLUSIONS Three primary immunotypes of resectable HCC (IE2, ITM and ID) were identified, and HG and lenvatinib could potentially overcome immune checkpoint blockade (ICB) resistance in ITM patients with HCC, particularly those classified as type III-IV.
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Affiliation(s)
- Jing-Xuan Xu
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Nanning, China
- Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumour, Ministry of Education, Nanning, China
| | - Yue-Xiang Su
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Nanning, China
- Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumour, Ministry of Education, Nanning, China
| | - Yuan-Yuan Chen
- Department of Ultrasound, First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Yi-Yue Huang
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Nanning, China
- Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumour, Ministry of Education, Nanning, China
| | - Zu-Shun Chen
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Yu-Chong Peng
- Department of General Surgery, Chongqing Hospital of Traditional Chinese Medicine, Chongqing, China
| | - Lu-Nan Qi
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Nanning, China
- Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumour, Ministry of Education, Nanning, China
- Guangxi Liver Cancer Diagnosis and Treatment Engineering and Technology Research Center, Nanning, China
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Qiu N, Xu C, Zhang Z, Wang R, Wei X, Xie Y, Wang S, Lu D, Wang K, Xu S, Shen C, Su R, Cen B, Liu Y, Shen Y, Xu X. Autologous tumoral esterase-driven therapeutic polymers sequentially orchestrated antigen-induction, STING activation and anti-angiogenesis for systemic cancer immune therapy. Biomaterials 2025; 320:123260. [PMID: 40138966 DOI: 10.1016/j.biomaterials.2025.123260] [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: 10/30/2024] [Revised: 02/23/2025] [Accepted: 03/15/2025] [Indexed: 03/29/2025]
Abstract
Effective cancer immune therapy requires the orchestration of antigen induction, presentation and T-cell activation, further enhanced by anti-angiogenesis treatment; therefore, multiple therapeutics are generally used for such combination therapy. Herein, we report esterase-hydrolysable cationic polymers, N-[3-((4-acetoxy benzyl) oxy)-3-oxopropyl]-N-methyl-quaternized PEI (ERP) and poly{N-[2-(acryloyl-oxy) ethyl]-N-[p-acetyloxyphenyl]-N,N-dimethylammonium chloride} (PQDMA), capable of simultaneously inducing tumor cell immunogenic cell death (ICD) to release antigens, activating the cGAS-STING pathways of tumor macrophages and dendritic cells, and releasing antiangiogenic agent p-hydroxybenzyl alcohol (HBA). Thus, intratumoral injection of ERP or PQDMA systemically boosted the anti-cancer immunities and inhibited tumor angiogenesis in mouse hepatocellular carcinoma and melanoma bilateral tumor models, leading to more effective tumor growth inhibition of both treated and abscopal untreated tumors than ICD alone induced by mitoxantrone and control cationic polymers. Further study using gene knockout mice and transcriptome sequencing analysis confirmed the involvement of cGAS-STING and type I IFN signaling pathways. This work demonstrates ERP and PQDMA as the first examples of inherent therapeutic polymers, accomplishing systemic tumor inhibition without combining other therapeutic agents.
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Affiliation(s)
- Nasha Qiu
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou, 310006, China.
| | - Chang Xu
- Zhejiang University School of Medicine, Hangzhou, 310058, Zhejiang, China
| | - Zhen Zhang
- Key Laboratory of Smart Biomaterials of Zhejiang Province and Key Laboratory of Biomass Chemical Engineering of the Ministry of Education of China, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou, 310058, China
| | - Rui Wang
- Zhejiang University School of Medicine, Hangzhou, 310058, Zhejiang, China
| | - Xuyong Wei
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou, 310006, China
| | - Yangla Xie
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou, 310006, China
| | - Shuai Wang
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou, 310006, China
| | - Di Lu
- School of Clinical Medicine, Hangzhou Medical College, Hangzhou, 310059, China
| | - Kai Wang
- School of Clinical Medicine, Hangzhou Medical College, Hangzhou, 310059, China
| | - Shengjun Xu
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou, 310006, China
| | - Chenchen Shen
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou, 310006, China
| | - Renyi Su
- Zhejiang University School of Medicine, Hangzhou, 310058, Zhejiang, China
| | - Beini Cen
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou, 310006, China
| | - Yanpeng Liu
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou, 310006, China
| | - Youqing Shen
- Key Laboratory of Smart Biomaterials of Zhejiang Province and Key Laboratory of Biomass Chemical Engineering of the Ministry of Education of China, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou, 310058, China.
| | - Xiao Xu
- School of Clinical Medicine, Hangzhou Medical College, Hangzhou, 310059, China; Institute of Translational Medicine, Zhejiang University, Hangzhou, 310058, China.
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Jing Z, Yinhang W, Jian C, Zhanbo Q, Xinyue W, Shuwen H. Interaction between gut microbiota and T cell immunity in colorectal cancer. Autoimmun Rev 2025; 24:103807. [PMID: 40139455 DOI: 10.1016/j.autrev.2025.103807] [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: 07/02/2024] [Revised: 02/26/2025] [Accepted: 03/22/2025] [Indexed: 03/29/2025]
Abstract
This review delves into the complex and multi-layered mechanisms that govern the interaction between gut microbiota and T cells in the context of colorectal cancer (CRC), revealing a novel "microbiota-immune regulatory landscape" within the tumor microenvironment. As CRC progresses, the gut microbiota experiences a significant transformation in both its composition and metabolic patterns. On one hand, specific microbial entities within the gut microbiota can directly engage with T cells, functioning as "immunological triggers" that shape T-cell behavior. Simultaneously, microbial metabolites, such as short-chain fatty acids and bile acids, serve as "molecular regulators" that intricately govern T-cell function and differentiation, fine-tuning the immune response. On the other hand, the quorum-sensing mechanism, a recently recognized communication network among bacteria, also plays a pivotal role in orchestrating T-cell immunity. Additionally, the gut microbiota forms an intriguing connection with the neuro-immune regulatory axis, a largely unexplored "territory" in CRC research. Regarding treatment strategies, a diverse array of intervention approaches-including dietary modifications, the utilization of probiotics, bacteriophages, and targeted antibiotic therapies-offer promising prospects for restoring the equilibrium of the gut microbiota, thereby acting as "ecosystem renovators" that impede tumor initiation and progression. Nevertheless, the current research landscape in this field is fraught with challenges. These include significant variations in microbial composition, dietary preferences, and tumor microenvironments among individuals, a lack of large-scale cohort studies, and insufficient research that integrates tumor mutation analysis, gut microbiota investigations, and immune microenvironment evaluations. This review emphasizes the necessity for future research efforts to seamlessly incorporate multiple factors and utilize bioinformatics analysis to construct a more comprehensive "interactive map" of the gut microbiota-T cell relationship in CRC. The aim is to establish a solid theoretical basis for the development of highly effective and personalized treatment regimens, ultimately transforming the therapeutic approach to CRC.
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Affiliation(s)
- Zhuang Jing
- Huzhou Central Hospital, Affiliated Central Hospital Huzhou University, No.1558, Sanhuan North Road, Wuxing District, Huzhou, Zhejiang Province 313000, People's Republic of China; Huzhou Central Hospital, Fifth School of Clinical Medicine of Zhejiang Chinese Medical University, No.1558, Sanhuan North Road, Wuxing District, Huzhou, Zhejiang Province 313000, People's Republic of China; Zhejiang-France United Laboratory of Integrated Traditional Chinese and Modern Medicine in Colorectal Cancer, No.1558, Sanhuan North Road, Wuxing District, Huzhou, Zhejiang Province 313000, People's Republic of China
| | - Wu Yinhang
- Huzhou Central Hospital, Affiliated Central Hospital Huzhou University, No.1558, Sanhuan North Road, Wuxing District, Huzhou, Zhejiang Province 313000, People's Republic of China; Huzhou Central Hospital, Fifth School of Clinical Medicine of Zhejiang Chinese Medical University, No.1558, Sanhuan North Road, Wuxing District, Huzhou, Zhejiang Province 313000, People's Republic of China; Zhejiang-France United Laboratory of Integrated Traditional Chinese and Modern Medicine in Colorectal Cancer, No.1558, Sanhuan North Road, Wuxing District, Huzhou, Zhejiang Province 313000, People's Republic of China
| | - Chu Jian
- Huzhou Central Hospital, Affiliated Central Hospital Huzhou University, No.1558, Sanhuan North Road, Wuxing District, Huzhou, Zhejiang Province 313000, People's Republic of China; Huzhou Central Hospital, Fifth School of Clinical Medicine of Zhejiang Chinese Medical University, No.1558, Sanhuan North Road, Wuxing District, Huzhou, Zhejiang Province 313000, People's Republic of China; Zhejiang-France United Laboratory of Integrated Traditional Chinese and Modern Medicine in Colorectal Cancer, No.1558, Sanhuan North Road, Wuxing District, Huzhou, Zhejiang Province 313000, People's Republic of China
| | - Qu Zhanbo
- Huzhou Central Hospital, Affiliated Central Hospital Huzhou University, No.1558, Sanhuan North Road, Wuxing District, Huzhou, Zhejiang Province 313000, People's Republic of China; Huzhou Central Hospital, Fifth School of Clinical Medicine of Zhejiang Chinese Medical University, No.1558, Sanhuan North Road, Wuxing District, Huzhou, Zhejiang Province 313000, People's Republic of China; Zhejiang-France United Laboratory of Integrated Traditional Chinese and Modern Medicine in Colorectal Cancer, No.1558, Sanhuan North Road, Wuxing District, Huzhou, Zhejiang Province 313000, People's Republic of China
| | - Wu Xinyue
- Huzhou Central Hospital, Affiliated Central Hospital Huzhou University, No.1558, Sanhuan North Road, Wuxing District, Huzhou, Zhejiang Province 313000, People's Republic of China; Huzhou Central Hospital, Fifth School of Clinical Medicine of Zhejiang Chinese Medical University, No.1558, Sanhuan North Road, Wuxing District, Huzhou, Zhejiang Province 313000, People's Republic of China; Zhejiang-France United Laboratory of Integrated Traditional Chinese and Modern Medicine in Colorectal Cancer, No.1558, Sanhuan North Road, Wuxing District, Huzhou, Zhejiang Province 313000, People's Republic of China
| | - Han Shuwen
- Huzhou Central Hospital, Affiliated Central Hospital Huzhou University, No.1558, Sanhuan North Road, Wuxing District, Huzhou, Zhejiang Province 313000, People's Republic of China; Huzhou Central Hospital, Fifth School of Clinical Medicine of Zhejiang Chinese Medical University, No.1558, Sanhuan North Road, Wuxing District, Huzhou, Zhejiang Province 313000, People's Republic of China; Zhejiang-France United Laboratory of Integrated Traditional Chinese and Modern Medicine in Colorectal Cancer, No.1558, Sanhuan North Road, Wuxing District, Huzhou, Zhejiang Province 313000, People's Republic of China; ASIR (Institute - Association of intelligent systems and robotics), 14B rue Henri Sainte Claire Deville, 92500 Rueil-Malmaison, France.
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Maruyama Y, Hosonuma M, Toyoda H, Funayama E, Sasaki A, Baba Y, Tajima K, Nakashima R, Sasaki A, Shida M, Tsurui T, Tsuji M, Tsunoda T, Shimane T, Kiuchi Y, Yoshimura K, Kuramasu A. Combination therapy with cetirizine and anti-PD-1 antibody suppresses colitis-induced colon tumor formation in mice. Eur J Pharmacol 2025; 999:177704. [PMID: 40320111 DOI: 10.1016/j.ejphar.2025.177704] [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: 12/08/2024] [Revised: 04/24/2025] [Accepted: 05/02/2025] [Indexed: 05/10/2025]
Abstract
Immune checkpoint inhibitors (ICIs) have transformed cancer therapy, yet their efficacy remains limited in inflammation-associated tumors, necessitating combinatorial approaches. Although combinations with cytotoxic or targeted agents are well established, the therapeutic potential of non-oncologic drugs, such as antihistamines, is less explored. In this study, we investigate whether cetirizine, a non-sedating histamine H1 receptor antagonist, enhances the antitumor effects of anti-programmed cell death protein 1 (PD-1) antibody in a murine model of colitis-associated colorectal cancer. Combination therapy, not monotherapy, significantly reduced tumor volume in vivo. Flow cytometry of splenocytes revealed increased PD-1 expression on T cells only in the combination group, suggesting systemic immune activation. Immunohistochemical analysis showed elevated CD3+ T-cell infiltration into tumors following combination treatment. Meanwhile, gene expression analysis of tumor tissues revealed downregulated Vegfa, Mmp9, Il10, and Cd80, along with upregulated Hspg2 and Fn1, suggesting a shift in the tumor microenvironment. In vitro, cetirizine suppressed Mmp9 expression in CT26 cells, Il10 in macrophages, and VEGFA in human umbilical vein endothelial cells, indicating cell-type-specific effects that partially mirror the in vivo findings. Immunohistochemistry further demonstrated a reduced frequency of FoxP3+ regulatory T cells among CD3+ T cells within the tumor stroma in the combination group. Collectively, these findings indicate that cetirizine enhances ICI efficacy by reshaping the tumor microenvironment through immunomodulatory mechanisms. Our results support the repurposing of antihistamines as a novel strategy to improve cancer immunotherapy.
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Affiliation(s)
- Yuki Maruyama
- Department of Clinical Immuno Oncology, Research Institute for Clinical Pharmacology and Therapeutics, Showa Medical University, Tokyo, Japan; Division of Medical Pharmacology, Department of Pharmacology, Showa Medical University School of Medicine, Tokyo, Japan; Pharmacological Research Center, Showa Medical University, Tokyo, Japan; Department of Otorhinolaryngology-Head and Neck Surgery, Showa Medical University School of Medicine, Tokyo, Japan
| | - Masahiro Hosonuma
- Department of Clinical Immuno Oncology, Research Institute for Clinical Pharmacology and Therapeutics, Showa Medical University, Tokyo, Japan; Division of Medical Pharmacology, Department of Pharmacology, Showa Medical University School of Medicine, Tokyo, Japan; Pharmacological Research Center, Showa Medical University, Tokyo, Japan; Division of Medical Oncology, Department of Medicine, Showa Medical University School of Medicine, Tokyo, Japan
| | - Hitoshi Toyoda
- Department of Clinical Immuno Oncology, Research Institute for Clinical Pharmacology and Therapeutics, Showa Medical University, Tokyo, Japan; Division of Medical Pharmacology, Department of Pharmacology, Showa Medical University School of Medicine, Tokyo, Japan; Pharmacological Research Center, Showa Medical University, Tokyo, Japan; Department of Orthopaedic Surgery, School of Medicine, Showa Medical University, Tokyo, Japan
| | - Eiji Funayama
- Department of Clinical Immuno Oncology, Research Institute for Clinical Pharmacology and Therapeutics, Showa Medical University, Tokyo, Japan; Pharmacological Research Center, Showa Medical University, Tokyo, Japan; Division of Pharmacology, Department of Pharmacology, Toxicology and Therapeutics, School of Pharmacy, Showa Medical University, Tokyo, Japan
| | - Akiko Sasaki
- Division of Medical Pharmacology, Department of Pharmacology, Showa Medical University School of Medicine, Tokyo, Japan; Pharmacological Research Center, Showa Medical University, Tokyo, Japan
| | - Yuta Baba
- Department of Clinical Immuno Oncology, Research Institute for Clinical Pharmacology and Therapeutics, Showa Medical University, Tokyo, Japan
| | - Kohei Tajima
- Department of Clinical Immuno Oncology, Research Institute for Clinical Pharmacology and Therapeutics, Showa Medical University, Tokyo, Japan
| | - Rie Nakashima
- Department of Clinical Immuno Oncology, Research Institute for Clinical Pharmacology and Therapeutics, Showa Medical University, Tokyo, Japan
| | - Aya Sasaki
- Department of Clinical Immuno Oncology, Research Institute for Clinical Pharmacology and Therapeutics, Showa Medical University, Tokyo, Japan; Division of Medical Pharmacology, Department of Pharmacology, Showa Medical University School of Medicine, Tokyo, Japan; Pharmacological Research Center, Showa Medical University, Tokyo, Japan
| | - Midori Shida
- Department of Clinical Immuno Oncology, Research Institute for Clinical Pharmacology and Therapeutics, Showa Medical University, Tokyo, Japan
| | - Toshiaki Tsurui
- Department of Clinical Immuno Oncology, Research Institute for Clinical Pharmacology and Therapeutics, Showa Medical University, Tokyo, Japan; Division of Medical Pharmacology, Department of Pharmacology, Showa Medical University School of Medicine, Tokyo, Japan; Pharmacological Research Center, Showa Medical University, Tokyo, Japan; Division of Medical Oncology, Department of Medicine, Showa Medical University School of Medicine, Tokyo, Japan
| | - Mayumi Tsuji
- Pharmacological Research Center, Showa Medical University, Tokyo, Japan
| | - Takuya Tsunoda
- Division of Medical Oncology, Department of Medicine, Showa Medical University School of Medicine, Tokyo, Japan
| | - Toshikazu Shimane
- Department of Clinical Immuno Oncology, Research Institute for Clinical Pharmacology and Therapeutics, Showa Medical University, Tokyo, Japan; Head and Neck Oncology Center, Showa Medical University, Tokyo, Japan
| | - Yuji Kiuchi
- Division of Medical Pharmacology, Department of Pharmacology, Showa Medical University School of Medicine, Tokyo, Japan; Pharmacological Research Center, Showa Medical University, Tokyo, Japan
| | - Kiyoshi Yoshimura
- Department of Clinical Immuno Oncology, Research Institute for Clinical Pharmacology and Therapeutics, Showa Medical University, Tokyo, Japan; Division of Medical Oncology, Department of Medicine, Showa Medical University School of Medicine, Tokyo, Japan
| | - Atsuo Kuramasu
- Department of Clinical Immuno Oncology, Research Institute for Clinical Pharmacology and Therapeutics, Showa Medical University, Tokyo, Japan.
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Hayashi H. Going forward in pleural mesothelioma: time for a shift from a single-entity treatment approach. Ann Oncol 2025; 36:478-480. [PMID: 39894353 DOI: 10.1016/j.annonc.2025.01.019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2025] [Revised: 01/22/2025] [Accepted: 01/23/2025] [Indexed: 02/04/2025] Open
Affiliation(s)
- H Hayashi
- Department of Medical Oncology, Kindai University Faculty of Medicine, Osaka-Sayama, Osaka, Japan.
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Shitara K, Janjigian YY, Ajani J, Moehler M, Yao J, Wang X, Chhibber A, Pandya D, Shen L, Garrido M, Gallardo C, Wyrwicz L, Yamaguchi K, Skoczylas T, Bragagnoli A, Liu T, Schenker M, Yañez P, Kowalyszyn R, Karamouzis M, Zander T, Feeney K, Elimova E, Doshi P, Li M, Lei M. Nivolumab plus chemotherapy or ipilimumab in gastroesophageal cancer: exploratory biomarker analyses of a randomized phase 3 trial. Nat Med 2025; 31:1519-1530. [PMID: 40055521 PMCID: PMC12092258 DOI: 10.1038/s41591-025-03575-0] [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: 05/08/2024] [Accepted: 02/07/2025] [Indexed: 05/22/2025]
Abstract
First-line nivolumab-plus-chemotherapy demonstrated superior overall survival (OS) and progression-free survival versus chemotherapy for advanced gastroesophageal adenocarcinoma with programmed death ligand 1 combined positive score ≥ 5, meeting both primary end points of the randomized phase 3 CheckMate 649 trial. Nivolumab-plus-ipilimumab provided durable responses and higher survival rates versus chemotherapy; however, the prespecified OS significance boundary was not met. To identify biomarkers predictive of differential efficacy outcomes, post hoc exploratory analyses were performed using whole-exome sequencing and RNA sequencing. Nivolumab-based therapies demonstrated improved efficacy versus chemotherapy in hypermutated and, to a lesser degree, Epstein-Barr virus-positive tumors compared with chromosomally unstable and genomically stable tumors. Within the KRAS-altered subgroup, only patients treated with nivolumab-plus-chemotherapy demonstrated improved OS benefit versus chemotherapy. Low stroma gene expression signature scores were associated with OS benefit with nivolumab-based regimens; high regulatory T cell signatures were associated with OS benefit only with nivolumab-plus-ipilimumab. Our analyses suggest that distinct and overlapping pathways contribute to the efficacy of nivolumab-based regimens in gastroesophageal adenocarcinoma.
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Affiliation(s)
- Kohei Shitara
- National Cancer Center Hospital East, Kashiwa, Japan
- Department of Immunology, Nagoya University Graduate School of Medicine, Aichi, Japan
| | - Yelena Y Janjigian
- Memorial Sloan Kettering Cancer Center, New York, NY, USA.
- Weill Cornell Medical College, New York, NY, USA.
| | - Jaffer Ajani
- The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | | | - Jin Yao
- Bristol Myers Squibb, Princeton, NJ, USA
| | - Xuya Wang
- Bristol Myers Squibb, Princeton, NJ, USA
- Daiichi Sankyo Inc, Basking Ridge, NJ, USA
| | | | - Dimple Pandya
- Bristol Myers Squibb, Princeton, NJ, USA
- Eli Lilly, Indianapolis, IN, USA
| | - Lin Shen
- Peking University Cancer Hospital and Institute, Beijing, China
| | - Marcelo Garrido
- Pontificia Universidad Católica-Universidad Mayor, Santiago, Chile
| | | | | | - Kensei Yamaguchi
- Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo, Japan
| | | | | | - Tianshu Liu
- Zhongshan Hospital Fudan University, Shanghai, China
| | | | | | | | | | | | - Kynan Feeney
- Notre Dame University and Edith Cowan University, Murdoch, Western Australia, Australia
| | - Elena Elimova
- Princess Margaret Cancer Centre, Toronto, Ontario, Canada
| | - Parul Doshi
- Bristol Myers Squibb, Princeton, NJ, USA
- Gilead Sciences, Foster City, CA, USA
| | | | - Ming Lei
- Bristol Myers Squibb, Princeton, NJ, USA.
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Yu H, Yang R, Li M, Li D, Xu Y. The role of Treg cells in colorectal cancer and the immunotherapy targeting Treg cells. Front Immunol 2025; 16:1574327. [PMID: 40308582 PMCID: PMC12040624 DOI: 10.3389/fimmu.2025.1574327] [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: 02/10/2025] [Accepted: 03/28/2025] [Indexed: 05/02/2025] Open
Abstract
Colorectal cancer (CRC) is among the most prevalent and lethal cancers globally, accounting for approximately 10% of all cancer cases and deaths. Regulatory T (Treg) cells, which accumulate in CRC tissue, suppress anti-tumor immune responses and facilitate tumor progression. This review discusses Treg cell origins and functions, along with the mechanisms by which Tregs influence CRC development. In addition, we highlight therapeutic strategies targeting Tregs-such as immune checkpoint inhibitors and combinatorial approaches-to enhance effector T cell responses. A deeper understanding of Treg-mediated immunosuppression in CRC may inform the design of more effective immunotherapies and precision medicine strategies.
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Affiliation(s)
- Hanqing Yu
- Department of General Surgery, The Sixth People’s Hospital of Huizhou, Huizhou, China
| | - Ruiliang Yang
- Department of General Surgery, The Sixth People’s Hospital of Huizhou, Huizhou, China
| | - Meixiang Li
- Department of General Surgery, The Sixth People’s Hospital of Huizhou, Huizhou, China
| | - Dan Li
- Department of Internal Medicine, The Sixth People’s Hospital of Huizhou, Huizhou, China
| | - Yuanqing Xu
- Department of General Surgery, The Sixth People’s Hospital of Huizhou, Huizhou, China
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Lim J, Goh MJ, Song BG, Sinn DH, Kang W, Gwak GY, Choi MS, Lee JH, Cha DI, Gu K, Ha SY, Hwang I, Park WY, Paik YH. Unraveling the immune-activated tumor microenvironment correlated with clinical response to atezolizumab plus bevacizumab in advanced HCC. JHEP Rep 2025; 7:101304. [PMID: 40124166 PMCID: PMC11929055 DOI: 10.1016/j.jhepr.2024.101304] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2024] [Revised: 12/05/2024] [Accepted: 12/10/2024] [Indexed: 03/25/2025] Open
Abstract
Background & Aims Despite atezolizumab plus bevacizumab being a standard treatment for advanced hepatocellular carcinoma (HCC), a significant proportion of patients do not achieve durable benefit. This study aimed to identify predictive biomarkers for this therapy by investigating the role of immune activation within the tumor microenvironment (TME). Methods We characterized the intratumoral TME of patients with advanced HCC treated with atezolizumab plus bevacizumab using single cell transcriptomics on pretreatment tumor biopsies from 12 patients. To complement and support these findings, we integrated our single cell data with publicly available bulk RNA-sequencing data from independent clinical trial cohorts. Results Patients who responded to combination therapy with atezolizumab plus bevacizumab demonstrated an immune-activated TME, marked by enhanced cytotoxicity and a tumor-specific T cell response. These patients also exhibited an increased proportion of inflammatory cytokine-enriched tumor-associated macrophage clusters with stronger interactions with T cells, an increased population of conventional dendritic cells, and activated antigen-presenting function in tumor endothelial cells. When publicly available bulk RNA-sequencing data from independent clinical trial cohorts were analyzed, these immune activation features were associated with improved progression-free survival (median 10.8 months, 95% CI: 7.3-not reached versus 5.5 months, 95% CI: 4.0-6.7; p <0.001). Conclusions These findings suggest that the existence of an activated immune TME before treatment is crucial for a favorable clinical response in patients with HCC treated with atezolizumab plus bevacizumab. Impact and implications Only a subset of patients with HCC benefit from combination therapy with atezolizumab plus bevacizumab, limiting its clinical utility. In this study, we used single cell RNA analysis to identify TME features associated with a clinical response to this therapy. Our findings suggest that a pre-existing immune-activated TME is crucial for predicting the response to atezolizumab plus bevacizumab. Specifically, features such as enhanced T cell cytotoxicity, inflammatory cytokine-enriched macrophage clusters, active antigen presentation in endothelial cells, and an increased presence of dendritic cells may aid patient selection and inform therapeutic strategies.
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Affiliation(s)
- Jinyeong Lim
- Department of Health Science and Technology, Samsung Advanced Institute for Health Science and Technology, Sunkyunkwan University, Seoul, South Korea
- Samsung Genome Institute, Samsung Medical Center, Seoul, South Korea
| | - Myung Ji Goh
- Division of Gastroenterology and Hepatology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Byeong Geun Song
- Division of Gastroenterology and Hepatology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Dong Hyun Sinn
- Division of Gastroenterology and Hepatology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Wonseok Kang
- Division of Gastroenterology and Hepatology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Geum-Youn Gwak
- Division of Gastroenterology and Hepatology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Moon Seok Choi
- Division of Gastroenterology and Hepatology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Joon Hyeok Lee
- Division of Gastroenterology and Hepatology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Dong Ik Cha
- Department of Radiology and Center for Imaging Science, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Kyowon Gu
- Department of Radiology and Center for Imaging Science, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Sang Yun Ha
- Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Inwoo Hwang
- Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Woong-Yang Park
- Department of Health Science and Technology, Samsung Advanced Institute for Health Science and Technology, Sunkyunkwan University, Seoul, South Korea
- Samsung Genome Institute, Samsung Medical Center, Seoul, South Korea
| | - Yong-Han Paik
- Department of Health Science and Technology, Samsung Advanced Institute for Health Science and Technology, Sunkyunkwan University, Seoul, South Korea
- Division of Gastroenterology and Hepatology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
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9
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Ma HR, Zhang D, Li L, Qi L, Wang L, Li YT, Wang YR. Targeted maintenance therapy for a young woman with cervical rhabdomyosarcoma: A case report and review of literature. World J Clin Oncol 2025; 16:101909. [PMID: 40130049 PMCID: PMC11866091 DOI: 10.5306/wjco.v16.i3.101909] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2024] [Revised: 11/19/2024] [Accepted: 12/05/2024] [Indexed: 01/21/2025] Open
Abstract
BACKGROUND Rhabdomyosarcoma of the uterine cervix is a rare form of soft-tissue sarcoma predominantly affecting young women, with no established standard treatment protocol. CASE SUMMARY This report presents a case of a 17-year-old female patient presenting with intermittent, non-cyclical vaginal bleeding and associated lower abdominal pain. Pelvic magnetic resonance imaging and additional examinations led to the diagnosis of cervical rhabdomyosarcoma. The primary treatment options for uterine cervical rhabdomyosarcoma include surgery, with or without adjuvant chemotherapy and radiotherapy. This patient underwent surgery followed by a postoperative chemotherapy regimen of gemcitabine combined with docetaxel and bevacizumab. After 19 months of follow-up, the patient showed no signs of recurrence and maintained good overall health. Given the rarity of cervix rhabdomyosarcoma, this case is presented to provide insights into the diagnosis and treatment of this condition. CONCLUSION This suggests that bevacizumab may demonstrate potential efficacy in the treatment of cervical rhabdomyosarcoma. In the future, targeted therapy is expected to play an increasingly significant role in the management of rhabdomyosarcoma.
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Affiliation(s)
- Huan-Ran Ma
- Department of Gynecologic Oncology, Affiliated Hospital of Qinghai University, Xining 810000, Qinghai Province, China
| | - Dan Zhang
- Department of Gynecologic Oncology, Affiliated Hospital of Qinghai University, Xining 810000, Qinghai Province, China
| | - Li Li
- Department of Gynecologic Oncology, Affiliated Hospital of Qinghai University, Xining 810000, Qinghai Province, China
| | - Lin Qi
- Department of Gynecologic Oncology, Affiliated Hospital of Qinghai University, Xining 810000, Qinghai Province, China
| | - Liang Wang
- Department of Gastrointestinal Oncology Surgery, Affiliated Hospital of Qinghai University, Xining 810000, Qinghai Province, China
| | - Yi-Tong Li
- Department of Gynecologic Oncology, Affiliated Hospital of Qinghai University, Xining 810000, Qinghai Province, China
| | - Ya-Ru Wang
- Department of Gynecologic Oncology, Affiliated Hospital of Qinghai University, Xining 810000, Qinghai Province, China
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10
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Pan H, Ruan M, Jin R, Zhang J, Li Y, Wu D, Zhang L, Sun W, Wang R. Immune checkpoint inhibitor plus tyrosine kinase inhibitor with or without transarterial chemoembolization for unresectable hepatocellular carcinoma. Front Oncol 2025; 15:1385304. [PMID: 40129919 PMCID: PMC11930818 DOI: 10.3389/fonc.2025.1385304] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2024] [Accepted: 02/11/2025] [Indexed: 03/26/2025] Open
Abstract
Background and aims Transcatheter arterial chemoembolization (TACE) has been combined with immune checkpoint inhibitor (ICI)-based systemic therapies for unresectable hepatocellular carcinoma (uHCC) with promising efficacy. However, whether the addition of TACE to the combination of ICI and tyrosine kinase inhibitor (TKI) (ICI+TKI+TACE) is superior to ICI+TKI combination therapy is still not clear. Thus, this study compares the efficacy of ICI+TKI+TACE triple therapy and ICI+TKI doublet therapy in patients with uHCC. Methods uHCC patients treated with either ICI+TKI+TACE triple therapy or ICI+TKI doublet therapy were retrospectively recruited between January 2016 and December 2021 at Eastern Hepatobiliary Surgery Hospital. The patients from ICI+TKI+TACE group and ICI+TKI group were further subjected to propensity score matching (PSM). The primary outcome was progression-free survival (PFS). The secondary outcomes were overall survival (OS) and objective response rate (ORR). Post-progression survival (PPS) as well as treatment-related adverse events (TRAEs) were also assessed. Results A total of 120 patients were matched. The median PFS was 8.4 months in ICI+TKI+TACE triple therapy group versus 6.6 months in ICI+TKI doublet therapy group (HR 0.72, 95%CI 0.48-1.08; p=0.115). Similar results were obtained in term of OS (26.9 versus 24.2 months, HR 0.88, 95% CI 0.51-1.52; p=0.670). The ORR in the triple therapy group was comparable with that in the doublet therapy group (16.6% versus 21.6%, p=0.487). Further subgroup analysis for PFS illustrated that patients without previous locoregional treatment (preLRT) (10.5 versus 3.7 months, HR 0.35 [0.16-0.76]; p=0.009), without previous treatment (10.5 versus 3.5 months, HR 0.34 [0.14-0.81]; p=0.015) or treated with lenvatinib (14.8 versus 6.9 months, HR 0.52 [0.31-0.87]; p=0.013) can significantly benefit from triple therapy compared with doublet therapy. A remarkable interaction between treatment and preLRT (p=0.049) or TKIs-combined (p=0.005) was also detected in term of PFS. Post progression treatment significantly improved PPS in both groups. The incidence of TRAEs was comparable between two groups. Conclusions The addition of TACE to ICI+TKI combination therapy did not result in a substantial improvement in efficacy and prognosis of patients. However, in selected uHCC patients (without preLRT or treated with lenvatinib as combination), ICI+TKI+TACE triple therapy may remarkably improve PFS.
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Affiliation(s)
- Hongyu Pan
- The First Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, The Naval Medical University, Shanghai, China
| | - Minghao Ruan
- The First Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, The Naval Medical University, Shanghai, China
| | - Riming Jin
- The First Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, The Naval Medical University, Shanghai, China
| | - Jin Zhang
- The First Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, The Naval Medical University, Shanghai, China
| | - Yao Li
- The First Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, The Naval Medical University, Shanghai, China
| | - Dong Wu
- The First Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, The Naval Medical University, Shanghai, China
| | - Lijie Zhang
- The Department of Information, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Wen Sun
- National Center for Liver Cancer, The Naval Medical University, Shanghai, China
| | - Ruoyu Wang
- The First Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, The Naval Medical University, Shanghai, China
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11
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Larrinaga G, Solano-Iturri JD, Arrieta-Aguirre I, Valdivia A, Lecumberri D, Iturregui AM, Lawrie CH, Armesto M, Dorado JF, Nunes-Xavier CE, Pulido R, López JI, Angulo JC. Prognostic and Therapeutic Implications of Alamandine Receptor MrgD Expression in Clear Cell Renal Cell Carcinoma with Development of Metastatic Disease. Biomolecules 2025; 15:387. [PMID: 40149923 PMCID: PMC11939982 DOI: 10.3390/biom15030387] [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: 01/14/2025] [Revised: 02/27/2025] [Accepted: 03/04/2025] [Indexed: 03/29/2025] Open
Abstract
Despite advances in the management of advanced clear cell renal cell carcinoma (ccRCC), robust biomarkers for prognosis and therapeutic response prediction remain elusive. Dysregulation of the intrarenal renin-angiotensin system (RAS) has been implicated in renal carcinogenesis but little explored, particularly regarding biomarker discovery and therapeutic innovation. Consequently, this study investigates the immunohistochemical expression and clinical relevance of the Mas-related G-protein-coupled receptor D (MrgD) in patients with ccRCC who developed metastatic disease (mccRCC). A cohort of 132 patients treated between 2008 and 2018 with nephrectomy and tyrosine kinase inhibitor (TKI)-based sequential therapy was analyzed. Treatment response was assessed using both the MASS and RECIST scoring systems. High MrgD expression in primary tumors was significantly associated with larger size, advanced stage, higher histological grade, and worse overall survival. Among 81 patients with metachronous metastases, high MrgD expression independently predicted shorter disease-free survival. High MrgD staining intensity correlated with poorer TKI responses in first-line therapy but improved outcomes with second-line mTORC1 inhibitors. These findings suggest that MrgD may be a useful biomarker of RAS linked to tumor aggressiveness in ccRCC. MrgD holds potential for identifying high-risk patients and guiding treatment selection in advanced disease. Further research is needed to unlock its clinical potential.
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MESH Headings
- Humans
- Carcinoma, Renal Cell/metabolism
- Carcinoma, Renal Cell/pathology
- Carcinoma, Renal Cell/drug therapy
- Carcinoma, Renal Cell/therapy
- Carcinoma, Renal Cell/genetics
- Male
- Female
- Middle Aged
- Kidney Neoplasms/pathology
- Kidney Neoplasms/metabolism
- Kidney Neoplasms/drug therapy
- Kidney Neoplasms/therapy
- Kidney Neoplasms/genetics
- Aged
- Prognosis
- Biomarkers, Tumor/metabolism
- Biomarkers, Tumor/genetics
- Receptors, G-Protein-Coupled/metabolism
- Receptors, G-Protein-Coupled/genetics
- Neoplasm Metastasis
- Protein Kinase Inhibitors/therapeutic use
- Adult
- Aged, 80 and over
- Nephrectomy
- Gene Expression Regulation, Neoplastic
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Affiliation(s)
- Gorka Larrinaga
- Department of Nursing, Faculty of Medicine and Nursing, University of the Basque Country (UPV/EHU), 48940 Leioa, Spain;
- Department of Physiology, Faculty of Medicine and Nursing, University of the Basque Country (UPV/EHU), 48940 Leioa, Spain
- Biobizkaia Health Research Institute, 48903 Barakaldo, Spain; (J.D.S.-I.); (C.E.N.-X.); (R.P.); (J.I.L.)
| | - Jon Danel Solano-Iturri
- Biobizkaia Health Research Institute, 48903 Barakaldo, Spain; (J.D.S.-I.); (C.E.N.-X.); (R.P.); (J.I.L.)
- Pathology Department, Cruces University Hospital, 48903 Barakaldo, Spain
| | - Inés Arrieta-Aguirre
- Department of Nursing, Faculty of Medicine and Nursing, University of the Basque Country (UPV/EHU), 48940 Leioa, Spain;
| | - Asier Valdivia
- Department of Cellular Biology and Histology, Faculty of Medicine and Nursing, University of the Basque Country (UPV/EHU), 48940 Leioa, Spain;
| | - David Lecumberri
- Department of Urology, Cruces University Hospital, 48903 Barakaldo, Spain; (D.L.); (A.M.I.)
| | - Ane Miren Iturregui
- Department of Urology, Cruces University Hospital, 48903 Barakaldo, Spain; (D.L.); (A.M.I.)
| | - Charles H. Lawrie
- Molecular Oncology Group, Biogipuzkoa Health Research Institute, 20014 San Sebastián, Spain; (C.H.L.); (M.A.)
- IKERBASQUE, Basque Foundation for Science, 48009 Bilbao, Spain
- Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DU, UK
- Sino-Swiss Institute of Advanced Technology (SSIAT), Shanghai University, Shanghai 201800, China
| | - María Armesto
- Molecular Oncology Group, Biogipuzkoa Health Research Institute, 20014 San Sebastián, Spain; (C.H.L.); (M.A.)
| | - Juan F. Dorado
- PeRTICA Statistical Solutions, Pl. Constitución, 2, 28943 Fuenlabrada, Spain;
| | - Caroline E. Nunes-Xavier
- Biobizkaia Health Research Institute, 48903 Barakaldo, Spain; (J.D.S.-I.); (C.E.N.-X.); (R.P.); (J.I.L.)
- Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, 0310 Oslo, Norway
| | - Rafael Pulido
- Biobizkaia Health Research Institute, 48903 Barakaldo, Spain; (J.D.S.-I.); (C.E.N.-X.); (R.P.); (J.I.L.)
- IKERBASQUE, Basque Foundation for Science, 48009 Bilbao, Spain
| | - José I. López
- Biobizkaia Health Research Institute, 48903 Barakaldo, Spain; (J.D.S.-I.); (C.E.N.-X.); (R.P.); (J.I.L.)
| | - Javier C. Angulo
- Clinical Department, Faculty of Medical Sciences, European University of Madrid, 28905 Getafe, Spain;
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12
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Guo X, Yang J, Cao R, Hao G. The interplay between angiogenesis-associated genes and molecular, clinical, and immune features in bladder cancer. Discov Oncol 2025; 16:265. [PMID: 40042726 PMCID: PMC11883062 DOI: 10.1007/s12672-025-01966-w] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2024] [Accepted: 02/11/2025] [Indexed: 03/09/2025] Open
Abstract
BACKGROUND Immunotherapy plays an important role in the treatment of bladder cancer (BLCA), with outcomes influenced by the tumor microenvironment (TME). Angiogenesis, a hallmark of cancer progression, shapes the TME and impacts immunotherapy efficacy. However, its specific role in BLCA remains underexplored. METHODS We analyzed 268 angiogenesis-related genes (ARGs) across ten gene sets using data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) cohorts. Through unsupervised clustering, we identified ARG-based subtypes and developed an ARG scoring system to quantify angiogenesis activity. The ARG score was correlated with clinical outcomes, immune cell infiltration, and immunotherapy response. Functional validation was performed using in vitro assays. RESULTS Two distinct ARG clusters exhibited significant differences in immune profiles, clinical outcomes, and functional characteristics. Patients in the high ARG cluster had poorer survival but showed enhanced responsiveness to immune checkpoint inhibitors (ICIs). The novel ARG score demonstrated strong predictive power for immunotherapy efficacy and survival outcomes. CONCLUSION ARG expression patterns profoundly impact the TME, clinical outcomes, and immunotherapy response in BLCA. The ARG score is a novel biomarker for stratifying patients and optimizing treatment strategies. These findings may contribute to clarifying the characteristics of TME and enable the exploration of more potent immunotherapy strategies.
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Affiliation(s)
- Xiaoxiao Guo
- Department of Urology, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China.
- Institute of Urology, Beijing Municipal Health Commission, Beijing, China.
| | - Jingxin Yang
- Department of Urology, National Center of Gerontology, Beijing Hospital, Beijing, China
- Medical School, University of Chinese Academy of Sciences, Beijing, China
| | - Rui Cao
- Department of Urology, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China
| | - Gangyue Hao
- Department of Urology, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China.
- Institute of Urology, Beijing Municipal Health Commission, Beijing, China.
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13
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Kertmen N, Kavgaci G, Koc I, Sagol SP, Isikay AI, Yazici G. Sequential immunotherapy and bevacizumab treatments in glioblastoma multiforme: A case series and review of the literature. Oncol Lett 2025; 29:146. [PMID: 39877061 PMCID: PMC11773301 DOI: 10.3892/ol.2025.14892] [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: 06/18/2024] [Accepted: 12/31/2024] [Indexed: 01/31/2025] Open
Abstract
Glioblastoma multiforme (GBM) is a tumor with a high refractory rate to immunotherapy and a low tumor mutational burden phenotype, leading to limited immunogenic neoantigens. The present study aimed to investigate the sequential use of immunotherapy and bevacizumab in patients with GBM, exploring the clinical outcomes and potential complications. Patients received various combinations of immunotherapy and bevacizumab after standard treatment, including surgery, radiotherapy and temozolomide. Clinical courses, radiological findings and treatment outcomes were monitored and documented during each clinical visit through routine physical examinations, imaging studies and review of medical records. The efficacy and side effects of this sequential drug approach remained unclear. The common features of these patients were a marked decline in cognitive function and clinical deterioration, assessed clinically in the absence of obvious tumor progression. Radiological evaluation was also performed, particularly for possible cerebrovascular events. In these cases, the potential for sequential treatment to suppress tumors while inducing cerebrovascular events was also investigated, and patients were not lost to overt tumor progression. Notably, further research is required to clarify the mechanisms of action and complications associated with the sequential use of immunotherapy and bevacizumab in the treatment of GBM.
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Affiliation(s)
- Neyran Kertmen
- Department of Medical Oncology, Hacettepe University Faculty of Medicine, Ankara, Ankara 06230, Turkey
| | - Gozde Kavgaci
- Department of Medical Oncology, Hacettepe University Faculty of Medicine, Ankara, Ankara 06230, Turkey
| | - Ilgin Koc
- Department of Medical Oncology, Hacettepe University Faculty of Medicine, Ankara, Ankara 06230, Turkey
| | - Safak Parlak Sagol
- Department of Radiology, Hacettepe University Faculty of Medicine, Ankara, Ankara 06230, Turkey
| | - Ahmet Ilkay Isikay
- Department of Neurosurgery, Hacettepe University Faculty of Medicine, Ankara, Ankara 06230, Turkey
| | - Gozde Yazici
- Department of Radiation Oncology, Hacettepe University Faculty of Medicine, Ankara, Ankara 06230, Turkey
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14
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Jiao J, Wu Y, Wu S, Jiang J. Enhancing Colorectal Cancer Treatment Through VEGF/VEGFR Inhibitors and Immunotherapy. Curr Treat Options Oncol 2025; 26:213-225. [PMID: 40045029 DOI: 10.1007/s11864-025-01306-8] [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] [Accepted: 02/17/2025] [Indexed: 03/20/2025]
Abstract
OPINION STATEMENT Colorectal cancer, ranking as the third most prevalent malignancy globally, substantially benefits from both immunotherapy and VEGF/VEGFR inhibitors. Nevertheless, the use of monotherapy proves inadequate in effectively tackling the heterogeneity of tumors and the intricacies of their microenvironment, frequently leading to drug resistance and immune evasion. This situation underscores the pressing need for innovative strategies aimed at augmenting the effectiveness and durability of treatments. Clinical research demonstrates that the combination of VEGF/VEGFR inhibitors (primarily including VEGF/VEGFR-targeted drugs and multi-kinase inhibitors) with immune checkpoint inhibitors creates a synergistic effect in the treatment of colorectal cancer. Our analysis explores how VEGF/VEGFR inhibitors recalibrate the tumor microenvironment, modulate immune cell functions, and influence the expression of immune checkpoints and cytokines. Furthermore, we critically evaluate the preclinical and clinical feasibility of these combined therapeutic approaches. Despite the potential for toxicity, the significant benefits and prospective applications of these strategies warrant thorough exploration. Exploring the synergistic mechanisms of these combined treatments has the potential to inaugurate a new paradigm in oncology, enabling more personalized and efficacious treatment modalities. Additionally, the synergy between VEGF/VEGFR inhibitors and nascent immunotherapies emerges as a promising field of inquiry.
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Affiliation(s)
- Jing Jiao
- Nanjing Medical University, Nanjing, 211166, Jiangsu, China
- Department of Tumor Biological Treatment, Institute of Cell Therapy, The Third Affiliated Hospital of Soochow University Jiangsu Engineering Research Center for Tumor Immunotherapy, Soochow University, Juqian Road №185, Changzhou, 213003, China
- Jiangsu Engineering Research Center for Tumor Immunotherapy, The Third Affiliated Hospital of Soochow University, Changzhou, 213003, Jiangsu, China
- Institute of Cell Therapy, The Third Affiliated Hospital of Soochow University, Changzhou, 213003, Jiangsu, China
| | - You Wu
- Department of Tumor Biological Treatment, Institute of Cell Therapy, The Third Affiliated Hospital of Soochow University Jiangsu Engineering Research Center for Tumor Immunotherapy, Soochow University, Juqian Road №185, Changzhou, 213003, China
- Jiangsu Engineering Research Center for Tumor Immunotherapy, The Third Affiliated Hospital of Soochow University, Changzhou, 213003, Jiangsu, China
- Institute of Cell Therapy, The Third Affiliated Hospital of Soochow University, Changzhou, 213003, Jiangsu, China
| | - Shaoxian Wu
- Department of Tumor Biological Treatment, Institute of Cell Therapy, The Third Affiliated Hospital of Soochow University Jiangsu Engineering Research Center for Tumor Immunotherapy, Soochow University, Juqian Road №185, Changzhou, 213003, China
- Jiangsu Engineering Research Center for Tumor Immunotherapy, The Third Affiliated Hospital of Soochow University, Changzhou, 213003, Jiangsu, China
- Institute of Cell Therapy, The Third Affiliated Hospital of Soochow University, Changzhou, 213003, Jiangsu, China
| | - Jingting Jiang
- Nanjing Medical University, Nanjing, 211166, Jiangsu, China.
- Department of Tumor Biological Treatment, Institute of Cell Therapy, The Third Affiliated Hospital of Soochow University Jiangsu Engineering Research Center for Tumor Immunotherapy, Soochow University, Juqian Road №185, Changzhou, 213003, China.
- Jiangsu Engineering Research Center for Tumor Immunotherapy, The Third Affiliated Hospital of Soochow University, Changzhou, 213003, Jiangsu, China.
- Institute of Cell Therapy, The Third Affiliated Hospital of Soochow University, Changzhou, 213003, Jiangsu, China.
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15
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Vizioli G, Nicoletti A, Feliciani D, Funaro B, Zileri Dal Verme L, Ponziani FR, Zocco MA, Gasbarrini A, Gabrielli M. Immunotherapy and MASLD-Related HCC: Should We Reconsider the Role of Etiology in the Therapeutic Approach to HCC? APPLIED SCIENCES 2025; 15:2279. [DOI: 10.3390/app15052279] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/21/2025]
Abstract
Hepatocellular carcinoma (HCC) accounts for 90% of primary liver cancers and typically arises in the context of chronic liver disease. With the increasing prevalence of metabolic disorders, metabolic dysfunction-associated steatotic liver disease (MASLD) has become the leading cause of chronic liver disease and the most rapidly increasing cause of HCC. The role of dysfunctional innate and adaptive immune responses in the development and progression of HCC is well-established, prompting numerous trials to evaluate the efficacy of immune checkpoint inhibitors (ICIs) in targeting tumor cells. These trials have yielded promising results, and ICIs, in combination with anti-vascular endothelial growth factor (VEGF) monoclonal antibodies, are now approved as first-line therapy for patients with metastatic or unresectable HCC, irrespective of the underlying liver disease. Notably, MASLD itself is characterized by immune system dysfunction, as metabolic inflammation plays a central role in its onset and progression. However, clinical studies and post-hoc analyses suggest that immunotherapy may be less effective in MASLD-associated HCC compared to viral-related HCC. This emerging evidence raises the question of whether the underlying liver disease influences the therapeutic response to ICIs in HCC. It may be time to consider tailoring therapeutic strategies for HCC based on the specific etiological, histological, and genotypical subgroups.
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Affiliation(s)
- Giuseppina Vizioli
- Department of Medical and Surgical Sciences, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Alberto Nicoletti
- Department of Medical and Surgical Sciences, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Daniela Feliciani
- Department of Medical and Surgical Sciences, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Barbara Funaro
- Department of Medical and Surgical Sciences, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Lorenzo Zileri Dal Verme
- Department of Medical and Surgical Sciences, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Francesca Romana Ponziani
- Department of Medical and Surgical Sciences, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Maria Assunta Zocco
- Department of Medical and Surgical Sciences, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Antonio Gasbarrini
- Department of Medical and Surgical Sciences, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Maurizio Gabrielli
- Department of Medical and Surgical Sciences, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
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16
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Zhao L, Xu C, Deng J, Ni Y. Enhanced antitumor activity of combined hepatic arterial infusion chemotherapy with Lenvatinib and PD-1 inhibitors in unresectable hepatocellular carcinoma: a meta-analysis. Front Oncol 2025; 15:1513394. [PMID: 40012555 PMCID: PMC11860986 DOI: 10.3389/fonc.2025.1513394] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2024] [Accepted: 01/28/2025] [Indexed: 02/28/2025] Open
Abstract
Background Hepatic arterial infusion chemotherapy (HAIC) is increasingly recognized as a primary treatment option for patients with unresectable hepatocellular carcinoma (uHCC), providing a focused treatment for localized tumors. The combination of lenvatinib, a multikinase inhibitor, with PD-1 inhibitors has demonstrated significant survival benefits in HCC. This meta-analysis aims to assess whether the integration of HAIC with lenvatinib and PD-1 inhibitors (referred to as the HAIC-L-P group) leads to better treatment effectiveness and security compared to lenvatinib and PD-1 inhibitors alone (L-P group) in uHCC. Methods An exhaustive search of the literature was conducted, including PubMed, the Cochrane Library, Embase, ClinicalTrials.gov, and Web of Science, from the start of each database until September 2024, to ensure a thorough and up-to-date compilation of relevant studies. Extract data on outcome measures such as overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and adverse events (AEs). Subsequently, meta-analyses were performed using RevMan 5.4 to quantitatively evaluate the aggregated effect of the HAIC-L-P regimen versus the L-P regimen alone. Results In our systematic meta-analysis of eight retrospective cohort studies, the HAIC-L-P regimen demonstrated markedly enhanced OS, with an HR of 0.54 (95% CI: 0.45-0.64; p < 0.00001), and enhanced 1-year and 2-year OS rates. Superior PFS was also observed in the HAIC-L-P group, with an HR of 0.64 (95% CI: 0.55-0.75; p < 0.0001), and higher 1-year and 2-year PFS rates. Response rates were markedly higher in the HAIC-L-P group, with an ORR risk ratio of 2.15 (95% CI: 1.84-2.50; p < 0.00001) and a DCR risk ratio of 1.28 (95% CI: 1.20-1.43; p < 0.0001). The AEs classified as grade 3 or above were elevated in the HAIC-L-P group, with notable risk ratios for vomiting, elevated AST, elevated ALT, thrombocytopenia, neutropenia, and hyperbilirubinemia. No life-threatening AEs were reported. Conclusion The HAIC-L-P regimen correlated with enhanced tumor responses and prolonged survival, alongside manageable adverse effects, indicating its potential as a viable therapeutic strategy for individuals afflicted with uHCC. Systematic review registration https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42024594109.
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Affiliation(s)
- Lingling Zhao
- Department of General Surgery, Sichuan Science City Hospital, Mianyang, China
| | - Cheng Xu
- Department of Hepatobiliary Surgery, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, China
| | - Jiewen Deng
- Department of General Surgery, Sichuan Science City Hospital, Mianyang, China
| | - Yang Ni
- Department of General Surgery, Sichuan Science City Hospital, Mianyang, China
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Shen G, Liu Z, Wang M, Zhao Y, Liu X, Hou Y, Ma W, Han J, Zhou X, Ren D, Zhao F, Li Z, Huang S, Chen Y, He Y, Liu Y, Zhu Z, Li Y, Li J, Da M, Mo H, Du F, Cui L, Bai J, Liu Z, Ma F, Zhao J. Neoadjuvant apatinib addition to sintilimab and carboplatin-taxane based chemotherapy in patients with early triple-negative breast cancer: the phase 2 NeoSAC trial. Signal Transduct Target Ther 2025; 10:41. [PMID: 39915443 PMCID: PMC11802755 DOI: 10.1038/s41392-025-02137-7] [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: 09/20/2024] [Revised: 01/03/2025] [Accepted: 01/10/2025] [Indexed: 02/09/2025] Open
Abstract
We aimed to evaluate the efficacy and safety of adding apatinib, to sintilimab and chemotherapy in the neoadjuvant treatment of early triple-negative breast cancer (TNBC). In the phase 2 NeoSAC trial, patients with early TNBC received six cycles of apatinib, sintilimab, nab-paclitaxel, and carboplatin followed by surgery. The primary endpoint was pathological complete response (pCR) rate. Specimens collected pre-neoadjuvant therapy and post-surgery were retained for comprehensive analysis of predictive biomarkers and the impact on the tumor microenvironment. Among 34 enrolled patients, 24 achieved pCR (70.6%; 95% confidence interval (CI), 53.0-85.3), and 79.4% (95% CI, 65.1-93.7) had residual cancer burden 0-I. Imaging evaluation showed 21 complete responses (61.8%) and 13 partial responses (38.2%). The most common grade 3-4 adverse events were leukopenia (47%), neutropenia (36%), and thrombocytopenia (24%). The 36-month disease-free survival rate stood at 94.1% with a median follow-up of 39.1 months. Notably, baseline high ImmuneScore, immune cell infiltration, and enrichment of interferon-related pathways correlated with pCR. Comparison of pre-neoadjuvant and post-surgery data revealed that the pCR group treated with this novel regimen exhibited an upregulation of distinct immune cell subsets, thereby activating the tumor microenvironment. Moreover, higher oxeiptosis scores were associated with an increased likelihood of achieving pCR. Following neoadjuvant therapy, the pCR group showed a decrease in oxeiptosis score, whereas the non-pCR group exhibited an increase. Our study suggests that apatinib, sintilimab combined with carboplatin and nab-paclitaxel chemotherapy showed a promising clinical activity and manageable safety profile in early TNBC and merits further study. ClinicalTrials.gov registration: NCT04722718.
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Affiliation(s)
- Guoshuang Shen
- Breast Disease Diagnosis and Treatment Center, Affiliated Hospital of Qinghai University, Affiliated Cancer Hospital of Qinghai University, Xining, China
| | - Zhilin Liu
- Breast Disease Diagnosis and Treatment Center, Affiliated Hospital of Qinghai University, Affiliated Cancer Hospital of Qinghai University, Xining, China
| | - Miaozhou Wang
- Breast Disease Diagnosis and Treatment Center, Affiliated Hospital of Qinghai University, Affiliated Cancer Hospital of Qinghai University, Xining, China
| | - Yi Zhao
- Breast Disease Diagnosis and Treatment Center, Affiliated Hospital of Qinghai University, Affiliated Cancer Hospital of Qinghai University, Xining, China
| | - Xinlan Liu
- Medical Oncology Department of General Hospital of Ningxia Medical University, Yinchuan, China
| | - Yujin Hou
- Medical Oncology Department of General Hospital of Ningxia Medical University, Yinchuan, China
| | - Wenbiao Ma
- Department of Oncology, 2nd Ward, Qinghai Provincial People's Hospital (Breast and Thyroid Surgery), Xining, China
| | - Jingqi Han
- Department of pathology, Affiliated Hospital of Qinghai University, Affiliated Cancer Hospital of Qinghai University, Xining, China
| | - Xiaofeng Zhou
- Department of pathology, Affiliated Hospital of Qinghai University, Affiliated Cancer Hospital of Qinghai University, Xining, China
| | - Dengfeng Ren
- Breast Disease Diagnosis and Treatment Center, Affiliated Hospital of Qinghai University, Affiliated Cancer Hospital of Qinghai University, Xining, China
| | - Fuxing Zhao
- Breast Disease Diagnosis and Treatment Center, Affiliated Hospital of Qinghai University, Affiliated Cancer Hospital of Qinghai University, Xining, China
| | - Zitao Li
- Breast Disease Diagnosis and Treatment Center, Affiliated Hospital of Qinghai University, Affiliated Cancer Hospital of Qinghai University, Xining, China
| | - Shifen Huang
- Breast Disease Diagnosis and Treatment Center, Affiliated Hospital of Qinghai University, Affiliated Cancer Hospital of Qinghai University, Xining, China
| | - Yongzhi Chen
- Breast Disease Diagnosis and Treatment Center, Affiliated Hospital of Qinghai University, Affiliated Cancer Hospital of Qinghai University, Xining, China
| | - Yingjian He
- Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Breast Center, Peking University Cancer Hospital & Institute, Beijing, China
| | - Yan Liu
- Department of Public Health, Medical College of Qinghai University, Xining, China
| | - Zijun Zhu
- Breast Disease Diagnosis and Treatment Center, Affiliated Hospital of Qinghai University, Affiliated Cancer Hospital of Qinghai University, Xining, China
| | - Yongxin Li
- Breast Disease Diagnosis and Treatment Center, Affiliated Hospital of Qinghai University, Affiliated Cancer Hospital of Qinghai University, Xining, China
| | - Jinming Li
- Breast Disease Diagnosis and Treatment Center, Affiliated Hospital of Qinghai University, Affiliated Cancer Hospital of Qinghai University, Xining, China
| | - Mengting Da
- Breast Disease Diagnosis and Treatment Center, Affiliated Hospital of Qinghai University, Affiliated Cancer Hospital of Qinghai University, Xining, China
| | - Hongnan Mo
- State Key Laboratory of Molecular Oncology, 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
| | - Feng Du
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing),The VIPII Gastrointestinal Cancer Division of Medical Department, Peking University Cancer Hospital and Institute, 52 Fucheng Rd, Haidian District, Beijing, China
| | - Liang Cui
- Geneplus-Beijing Institute, Beijing, China
| | - Jing Bai
- Geneplus-Beijing Institute, Beijing, China
| | - Zhen Liu
- Breast Disease Diagnosis and Treatment Center, Affiliated Hospital of Qinghai University, Affiliated Cancer Hospital of Qinghai University, Xining, China.
| | - Fei Ma
- State Key Laboratory of Molecular Oncology, 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.
| | - Jiuda Zhao
- Breast Disease Diagnosis and Treatment Center, Affiliated Hospital of Qinghai University, Affiliated Cancer Hospital of Qinghai University, Xining, China.
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Guo H, Miao L, Yu C. The efficacy of targeted therapy and/or immunotherapy with or without chemotherapy in patients with colorectal cancer: A network meta-analysis. Eur J Pharmacol 2025; 988:177219. [PMID: 39716565 DOI: 10.1016/j.ejphar.2024.177219] [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: 08/22/2024] [Revised: 12/17/2024] [Accepted: 12/18/2024] [Indexed: 12/25/2024]
Abstract
BACKGROUND The use of targeted drugs and immunotherapy has significantly impacted the treatment of Colorectal Cancer. However, horizontal comparison among various regimens is extremely rare. Therefore, we evaluated the survival efficacy of multiple treatment regimens of targeted therapy and/or immunotherapy with or without chemotherapy in patients with Colorectal Cancer. METHODS A systematic search was conducted in PubMed, EMBASE, and Cochrane databases, covering the period from the establishment of the databases to October 29, 2024. To obtain articles that met the inclusion and exclusion criteria and contained the required data for conducting a network meta-analysis (NMA). The NMA evaluated overall survival (OS) and progression-free survival (PFS). RESULTS A total of 90 studies were identified, comprising a sample size of 33,167 subjects. In terms of PFS, compared with simple chemotherapy strategies, most of the other single or combined strategies are significantly effective, among which targeted therapy strategies have more advantages. Encorafenib + Binimetinib + Cetuximab (ENC-BIN-CET) shows significant benefits in all comparisons except when compared with Chemotherapy + Cetuximab + Dalotuzumab (Chemo-CET-DAL), Encorafenib + Cetuximab (ENC-CET), and Panitumumab + Sotorasib (PAN-SOT). The ENC-CET and PAN-SOT targeted strategies also show significant benefits. Pembrolizumab (PEM) monotherapy has advantages over all others except when it is not superior to some targeted strategies. Chemotherapy + Bevacizumab + Atezolizumab is only inferior to some strategies. In terms of OS, the combinations of Chemotherapy + Bevacizumab, ENC-CET, Chemotherapy + Panitumumab, and ENC-BIN-CET are superior to simple chemotherapy regimens. ENC-BIN-CET shows OS benefits in all comparisons except some. ENC-CET significantly improves OS in most cases, and PEM also significantly improves OS in some regimens. In the probability ranking of OS and PFS, ENC-BIN-CET has the best effect, followed by ENC-CET. CONCLUSIONS In conclusion, pembrolizumab is still effective in prolonging survival. Dual- and triple-drug targeted strategies are the best in terms of OS and PFS, and the combination of targeted immunotherapy and chemotherapy also works. However, not all combinations are beneficial. As targeted drugs play an active role, specific drugs for colorectal cancer regimens should be carefully selected.
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Affiliation(s)
- Haoyan Guo
- Nanhai Hospital of Traditional Chinese Medicine, Jinan University, No.16, Guicheng South Fifth Road, Foshan, Guangdong, 528200, China; Jinan University, Guangzhou, 510632, China
| | - Longjie Miao
- Shenzhen Hospital of Integrated Traditional Chinese and Western Medicine, Shenzhen, Guangdong, 518104, China; Guangzhou University of Chinese Medicine, Guangzhou, 510006, China
| | - Chengdong Yu
- Nanhai Hospital of Traditional Chinese Medicine, Jinan University, No.16, Guicheng South Fifth Road, Foshan, Guangdong, 528200, China; Jinan University, Guangzhou, 510632, China; Guangzhou University of Chinese Medicine, Guangzhou, 510006, China.
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19
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Sheng H, Luo Y, Zhong L, Wang Z, Sun Z, Gao X, He X, Zhu Z, Wu D, Sun J, Cao C. Antiangiogenic Treatment Facilitates the Abscopal Effect of Radiation Therapy Combined With Anti-PD-1 in Hepatocellular Carcinoma. Int J Radiat Oncol Biol Phys 2025; 121:534-546. [PMID: 39299549 DOI: 10.1016/j.ijrobp.2024.09.024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2024] [Revised: 09/02/2024] [Accepted: 09/08/2024] [Indexed: 09/22/2024]
Abstract
PURPOSE Metastasis is one of the most important factors contributing to poor prognosis in hepatocellular carcinoma. Radiation therapy (RT), along with its induced abscopal effect, is a promising treatment for metastatic patients. However, the incidence of abscopal effect in clinical practice is rare, even when RT is combined with immune checkpoint inhibitors (ICIs). In this study, we aim to investigate the role of antiangiogenic treatment on the abscopal effect induced by RT + ICIs. METHODS AND MATERIALS Bilateral subcutaneous and orthotopic Hepa1-6 and Hep53.4 models were established and treated with different combination treatments. We evaluated changes in the immune microenvironment and vascular normalization by flow cytometry, T cell receptor sequencing, chemotactic gene array, enzyme linked immunosorbent assays, and immunofluorescence. RESULTS Our studies showed that antiangiogenic treatment with RT + ICIs increased the antitumor response of the unirradiated lesions. Mechanistically, the blockade of vascular endothelial receptor 2 (anti-VEGFR2) increased the activation and maturation of dendritic cells and promoted the production of CD8+ T cells in irradiated tumors. These CD8+ T cells were attracted by anti-VEGFR2-induced CCL5 secretion from M1 macrophages in unirradiated tumors. Besides that, anti-VEGFR2 enhanced the function of CD8+ T cells by reducing myeloid-derived suppressor cells and regulatory T cells. CONCLUSIONS This study demonstrated that the combination of antiangiogenic treatment with RT and ICIs enhanced the abscopal effects. The application of triple therapy and its induced abscopal effect may offer a novel therapeutic approach for hepatocellular carcinoma, particularly for cases with multiple metastatic lesions.
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Affiliation(s)
- Hailong Sheng
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China; Cancer Center, Department of Radiation Oncology, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Yongyi Luo
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Liting Zhong
- Department of Oncology, Ganzhou Hospital-Nanfang Hospital, Southern Medical University, Guangzhou, China; Department of Oncology, Ganzhou People's Hospital, Ganzhou, China
| | - Zhiyi Wang
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Zhichao Sun
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Xinna Gao
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Xinrong He
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Zhenru Zhu
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Dehua Wu
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China; Guangdong Provincial Key Laboratory for Prevention and Control of Major Liver Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China.
| | - Jingyuan Sun
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China; Guangdong Provincial Key Laboratory for Prevention and Control of Major Liver Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China.
| | - Chuanhui Cao
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China; Guangdong Provincial Key Laboratory for Prevention and Control of Major Liver Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China.
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Sharma P, Chida K, Wu R, Tung K, Hakamada K, Ishikawa T, Takabe K. VEGFA Gene Expression in Breast Cancer Is Associated With Worse Prognosis, but Better Response to Chemotherapy and Immunotherapy. World J Oncol 2025; 16:120-130. [PMID: 39850522 PMCID: PMC11750749 DOI: 10.14740/wjon1993] [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: 10/23/2025] [Accepted: 01/02/2025] [Indexed: 01/25/2025] Open
Abstract
Background Vascular endothelial growth factor-A (VEGFA) is a key inducer of angiogenesis, responsible for generating new blood vessels in the tumor microenvironment (TME) and facilitating metastasis. Notably, Avastin, which targets VEGFA, failed to demonstrate any significant benefit in clinical trials for breast cancer (BC). This study aimed to investigate the clinical relevance of VEGFA gene expression in BC. Methods A total of 7,336 BC patients across eight independent cohorts: ISPY2 (GSE173839), Sweden Cancerome Analysis Network-Breast (SCAN-B) (GSE96058), Molecular Taxonomy of Breast Cancer International Consortium (METABRIC), GSE25066, GSE163882, GSE34138, GSE20194, and The Cancer Genome Atlas (TCGA), were analyzed. The calculated median VEGFA expression level was used to stratify these cohorts into high and low groups. Results High VEGFA was associated with worse disease-free, disease-specific, and overall survival in the METABRIC cohort, with findings supported by the SCAN-B cohort, which also showed worse overall survival (all P < 0.02). High VEGFA expression was seen in triple-negative breast cancer (TNBC) but not in BC with lymph node metastasis. Additionally, there was a significant correlation between high VEGFA expression and higher silent and non-silent mutations, single-nucleotide variant (SNV) neoantigens, homologous recombination defect, intratumoral heterogeneity, in the TCGA cohort. In the TCGA, METABRIC, and SCAN-B cohorts, high VEGFA BC was also associated with higher cell proliferation: higher Ki67 gene expression, higher Nottingham histological grade, and consistent enrichment of all the Hallmark cell proliferation-related gene sets. Unexpectedly, the angiogenesis gene set was not enriched in any of the cohorts and showed no association with infiltrations of lymphatic or blood vascular endothelial cells besides pericytes. High VEGFA BC had significantly less infiltration of anti-cancer immune cells but higher infiltration of pro-cancer immune cells in TCGA, METABRIC, and SCAN-B cohorts. Interestingly, BC, which had a pathological complete response (pCR) after anthracycline- and taxane-based neoadjuvant therapy, was associated with significantly heightened VEGFA expression in both estrogen receptor (ER)+/human epidermal growth factor receptor 2 (HER2)- and TNBC subtypes in the GSE25066 cohort and after immunotherapy in ER+/ HER2- subtype, but not TNBC in the ISPY2 cohort. Conclusions Our research indicates that high VEGFA BC confers high cell proliferation, reduced immune cell infiltration, and poorer survival, but allows better response to anthracycline- and taxane-based chemotherapy, and immunotherapy.
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Affiliation(s)
- Pia Sharma
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14203, USA
| | - Kohei Chida
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14203, USA
- Department of Gastroenterological Surgery, Hirosaki University Graduate School of Medicine, Hirosaki 036-8562, Japan
| | - Rongrong Wu
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14203, USA
- Department of Breast Surgery and Oncology, Tokyo Medical University, Tokyo 160-8402, Japan
| | - Kaity Tung
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14203, USA
- Department of Surgery, Jacobs School of Medicine and Biomedical Sciences, State University of New York, Buffalo, NY 14203, USA
| | - Kenichi Hakamada
- Department of Gastroenterological Surgery, Hirosaki University Graduate School of Medicine, Hirosaki 036-8562, Japan
| | - Takashi Ishikawa
- Department of Breast Surgery and Oncology, Tokyo Medical University, Tokyo 160-8402, Japan
| | - Kazuaki Takabe
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14203, USA
- Department of Breast Surgery and Oncology, Tokyo Medical University, Tokyo 160-8402, Japan
- Department of Surgery, Jacobs School of Medicine and Biomedical Sciences, State University of New York, Buffalo, NY 14203, USA
- Department of Breast and Thyroid Surgery, Yokohama City University Medical Center, Yokohama, Kanagawa, Japan
- Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8520, Japan
- Department of Breast Surgery, Fukushima Medical University School of Medicine, Fukushima 960-1295, Japan
- Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14203, USA
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21
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Famta P, Shah S, Vambhurkar G, Pandey G, Bagasariya D, Kumar KC, Prasad SB, Shinde A, Wagh S, Srinivasarao DA, Kumar R, Khatri DK, Asthana A, Srivastava S. Amelioration of breast cancer therapies through normalization of tumor vessels and microenvironment: paradigm shift to improve drug perfusion and nanocarrier permeation. Drug Deliv Transl Res 2025; 15:389-406. [PMID: 39009931 DOI: 10.1007/s13346-024-01669-9] [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] [Accepted: 07/04/2024] [Indexed: 07/17/2024]
Abstract
Breast cancer (BC) is the most commonly diagnosed cancer among women. Chemo-, immune- and photothermal therapies are employed to manage BC. However, the tumor microenvironment (TME) prevents free drugs and nanocarriers (NCs) from entering the tumor premises. Formulation scientists rely on enhanced permeation and retention (EPR) to extravasate NCs in the TME. However, recent research has demonstrated the inconsistent nature of EPR among different patients and tumor types. In addition, angiogenesis, high intra-tumor fluid pressure, desmoplasia, and high cell and extracellular matrix density resist the accumulation of NCs in the TME. In this review, we discuss TME normalization as an approach to improve the penetration of drugs and NCSs in the tumor premises. Strategies such as normalization of tumor vessels, reversal of hypoxia, alleviation of high intra-tumor pressure, and infiltration of lymphocytes for the reversal of therapy failure have been discussed in this manuscript. Strategies to promote the infiltration of anticancer immune cells in the TME after vascular normalization have been discussed. Studies strategizing time points to administer TME-normalizing agents are highlighted. Mechanistic pathways controlling the angiogenesis and normalization processes are discussed along with the studies. This review will provide greater tumor-targeting insights to the formulation scientists.
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Affiliation(s)
- Paras Famta
- Pharmaceutical Innovation and Translational Research Lab (PITRL), Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Balanagar, Hyderabad, 500037, Telangana, India
| | - Saurabh Shah
- Pharmaceutical Innovation and Translational Research Lab (PITRL), Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Balanagar, Hyderabad, 500037, Telangana, India
| | - Ganesh Vambhurkar
- Pharmaceutical Innovation and Translational Research Lab (PITRL), Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Balanagar, Hyderabad, 500037, Telangana, India
| | - Giriraj Pandey
- Pharmaceutical Innovation and Translational Research Lab (PITRL), Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Balanagar, Hyderabad, 500037, Telangana, India
| | - Deepkumar Bagasariya
- Pharmaceutical Innovation and Translational Research Lab (PITRL), Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Balanagar, Hyderabad, 500037, Telangana, India
| | - Kondasingh Charan Kumar
- Pharmaceutical Innovation and Translational Research Lab (PITRL), Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Balanagar, Hyderabad, 500037, Telangana, India
| | - Sajja Bhanu Prasad
- Pharmaceutical Innovation and Translational Research Lab (PITRL), Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Balanagar, Hyderabad, 500037, Telangana, India
| | - Akshay Shinde
- Pharmaceutical Innovation and Translational Research Lab (PITRL), Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Balanagar, Hyderabad, 500037, Telangana, India
| | - Suraj Wagh
- Pharmaceutical Innovation and Translational Research Lab (PITRL), Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Balanagar, Hyderabad, 500037, Telangana, India
| | - Dadi A Srinivasarao
- Pharmaceutical Innovation and Translational Research Lab (PITRL), Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Balanagar, Hyderabad, 500037, Telangana, India
| | - Rahul Kumar
- Department of Biological Sciences, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, India
| | - Dharmendra Kumar Khatri
- Department of Biological Sciences, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, India
- Molecular and Cellular Biology Laboratory, Department of Pharmacology, Nims Institute of Pharmacy, Nims University, Jaipur, Rajasthan, India
| | - Amit Asthana
- Department of Medical Devices, National Institute of Pharmaceutical Education and Research, Hyderabad, India
| | - Saurabh Srivastava
- Pharmaceutical Innovation and Translational Research Lab (PITRL), Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Balanagar, Hyderabad, 500037, Telangana, India.
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Kokkotou E, Grapsa D, Papadopoulou A, Gaitanakis S, Bakakos P, Poulakou G, Moutsatsou P, Syrigos K. Soluble PD-L1 and Serum Vascular Endothelial Growth Factor-B May Independently Predict Prognosis in Patients with Advanced Non-Small Cell Lung Cancer Treated with Pembrolizumab. Cancers (Basel) 2025; 17:421. [PMID: 39941790 PMCID: PMC11816055 DOI: 10.3390/cancers17030421] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2024] [Revised: 01/10/2025] [Accepted: 01/24/2025] [Indexed: 02/16/2025] Open
Abstract
Background: Previous preclinical data have shown that the dynamic cross-talk between abnormal tumor vasculature and immune cell factors in the tumor microenvironment may exert a critical role in the progression and treatment resistance of non-small cell lung cancer (NSCLC). In the clinical setting, a variety of blood-based angiogenesis- and immune-related factors are being increasingly investigated as potential biomarkers of prognosis or treatment response in immunotherapy-treated NSCLC. We herein aimed to evaluate the clinical relevance of the peripheral blood levels of vascular endothelial growth factor-A and -B (VEGF-A and VEGF-B, respectively), soluble programmed cell death-1 (sPD-1), and programmed cell death-ligand 1 (sPD-L1) in patients with advanced NSCLC treated with immune checkpoint inhibitors (ICIs). Methods: Consecutive patients with advanced-stage, non-oncogene-addicted NSCLC, eligible to receive ICIs at the Oncology Unit of Sotiria Athens General Hospital, were prospectively recruited. A group of sex- and age-matched healthy controls was also enrolled for the evaluation of the potential diagnostic significance of the examined biomarkers. Serum levels of all biomarkers were measured using ELISA, both before and after treatment, and were correlated with standard clinicopathological features of patients, treatment response, progression-free survival (PFS), and overall survival (OS). Results: A total of 55 patients and 16 healthy controls were included in the final analysis. The mean age of patients and controls was 66.5 years (SD = 8.0 years) and 65.4 years (SD = 9.1 years), respectively. The majority of patients (65.5%) received pembrolizumab in combination with chemotherapy, while the remaining patients received pembrolizumab monotherapy. ROC curve analysis showed that VEGFB and sPD-1 were the only markers with a significant diagnostic value. Higher pre-treatment values of sPD-L1 (HR = 1.68; p = 0.040) and sPD-1 (HR = 10.96; p = 0.037) as well as higher post-treatment values of VEGF-B (HR = 2.99; p = 0.049) were all significantly associated with a reduced OS in univariate Cox regression analysis. The adverse prognostic significance of higher pre-treatment values of sPD-L1 (HR = 2.10; p = 0.014) and higher post-treatment values of VEGFB (HR = 3.37; p = 0.032) was further confirmed in multivariate analysis. Conclusions: Our study results suggest that serum levels of sPD-L1 and VEGF-B may independently predict prognosis in ICI-treated advanced-stage NSCLC.
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Affiliation(s)
- Eleni Kokkotou
- Oncology Unit, 3rd Department of Internal Medicine, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (D.G.); (S.G.); (G.P.); (K.S.)
| | - Dimitra Grapsa
- Oncology Unit, 3rd Department of Internal Medicine, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (D.G.); (S.G.); (G.P.); (K.S.)
| | - Anna Papadopoulou
- Laboratory of Clinical Biochemistry, “Attikon” University General Hospital, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (A.P.); (P.M.)
| | - Stylianos Gaitanakis
- Oncology Unit, 3rd Department of Internal Medicine, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (D.G.); (S.G.); (G.P.); (K.S.)
| | - Petros Bakakos
- 1st Respiratory Medicine Department, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece;
| | - Garyfallia Poulakou
- Oncology Unit, 3rd Department of Internal Medicine, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (D.G.); (S.G.); (G.P.); (K.S.)
| | - Paraskevi Moutsatsou
- Laboratory of Clinical Biochemistry, “Attikon” University General Hospital, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (A.P.); (P.M.)
| | - Konstantinos Syrigos
- Oncology Unit, 3rd Department of Internal Medicine, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (D.G.); (S.G.); (G.P.); (K.S.)
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Wu FD, Zhou HF, Yang W, Zhu D, Wu BF, Shi HB, Liu S, Zhou WZ. Transarterial chemoembolization combined with lenvatinib and sintilimab vs lenvatinib alone in intermediate-advanced hepatocellular carcinoma. World J Gastrointest Oncol 2025; 17:96267. [PMID: 39817120 PMCID: PMC11664616 DOI: 10.4251/wjgo.v17.i1.96267] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2024] [Revised: 10/16/2024] [Accepted: 11/05/2024] [Indexed: 12/12/2024] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is the most common form of liver cancer that has limited treatment options and a poor prognosis. Transarterial chemoembolization (TACE) is the first-line treatment for intermediate-stage HCC but can induce tumour hypoxia, thereby promoting angiogenesis. Recent studies suggested that combining TACE with anti-angiogenic therapies and immunotherapy might improve efficacy. Lenvatinib, a tyrosine kinase inhibitor, has demonstrated superior outcomes compared to sorafenib, while immune checkpoint inhibitors such as sintilimab show potential when combined with TACE. However, the efficacy and safety of TACE combined with lenvatinib and sintilimab (TACE + SL) compared to TACE with lenvatinib alone (TACE + L) in patients with intermediate-advanced HCC has not yet been investigated. AIM To evaluate the efficacy and safety of TACE + SL therapy in comparison to TACE + L therapy in patients with intermediate-advanced HCC. METHODS A retrospective analysis was performed on patients with intermediate-advanced HCC who received TACE plus lenvatinib with or without sintilimab between September 2019 and September 2022. Baseline characteristics were compared, and propensity score matching was applied. Overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) were evaluated between the two groups, and adverse events were analyzed. RESULTS The study included 57 patients, with 30 in the TACE + SL group and 27 in the TACE + L group. The TACE + SL group demonstrated significantly improved median PFS and OS compared to the TACE + L group (PFS: 14.1 months vs 9.6 months, P = 0.016; OS: 22.4 months vs 14.1 months, P = 0.039), along with a higher ORR (70.0% vs 55.6%). After propensity score matching, 30 patients were included, with the TACE + SL group again showing longer median PFS and a trend toward improved OS (PFS: 14.6 months vs 9.2 months, P = 0.012; OS: 23.9 months vs 16.3 months, P = 0.063), and a higher ORR (73.3% vs 53.3%). No severe adverse events were reported. CONCLUSION TACE + SL demonstrated superior outcomes in terms of OS and PFS, compared to TACE + L. These findings suggest that the addition of sintilimab might enhance the therapeutic response in patients with intermediate-advanced HCC.
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Affiliation(s)
- Fei-Da Wu
- Department of Interventional Radiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu Province, China
| | - Hai-Feng Zhou
- Department of Interventional Radiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu Province, China
| | - Wei Yang
- Department of Interventional Radiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu Province, China
| | - Di Zhu
- Department of Interventional Radiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu Province, China
| | - Bi-Fei Wu
- Department of Interventional Radiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu Province, China
| | - Hai-Bin Shi
- Department of Interventional Radiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu Province, China
| | - Sheng Liu
- Department of Interventional Radiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu Province, China
| | - Wei-Zhong Zhou
- Department of Interventional Radiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu Province, China
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24
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Dai Y, Dong C, Wang Z, Zhou Y, Wang Y, Hao Y, Chen P, Liang C, Li G. Infiltrating T lymphocytes and tumor microenvironment within cholangiocarcinoma: immune heterogeneity, intercellular communication, immune checkpoints. Front Immunol 2025; 15:1482291. [PMID: 39845973 PMCID: PMC11750830 DOI: 10.3389/fimmu.2024.1482291] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2024] [Accepted: 12/17/2024] [Indexed: 01/24/2025] Open
Abstract
Cholangiocarcinoma is the second most common primary liver cancer, and its global incidence has increased in recent years. Radical surgical resection and systemic chemotherapy have traditionally been the standard treatment options. However, the complexity of cholangiocarcinoma subtypes often presents a challenge for early diagnosis. Additionally, high recurrence rates following radical treatment and resistance to late-stage chemotherapy limit the benefits for patients. Immunotherapy has emerged as an effective strategy for treating various types of cancer, and has shown efficacy when combined with chemotherapy for cholangiocarcinoma. Current immunotherapies targeting cholangiocarcinoma have predominantly focused on T lymphocytes within the tumor microenvironment, and new immunotherapies have yielded unsatisfactory results in clinical trials. Therefore, it is essential to achieve a comprehensive understanding of the unique tumor microenvironment of cholangiocarcinoma and the pivotal role of T lymphocytes within it. In this review, we describe the heterogeneous immune landscape and intercellular communication in cholangiocarcinoma and summarize the specific distribution of T lymphocytes. Finally, we review potential immune checkpoints in cholangiocarcinoma.
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Affiliation(s)
- Yunyan Dai
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, China
| | - Chenyang Dong
- First Clinical Medical College, Shanxi Medical University, Taiyuan, China
| | - Zhiming Wang
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, China
| | - Yunpeng Zhou
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, China
| | - Yi Wang
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, China
| | - Yi Hao
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, China
| | - Pinggui Chen
- Department of Nuclear Medicine, Nanyang First People’s Hospital, Nanyang, Henan, China
| | - Chaojie Liang
- First Clinical Medical College, Shanxi Medical University, Taiyuan, China
- Department of biliary and Pancreatic Surgery, First Hospital of Shanxi Medical University, Taiyuan, China
| | - Gaopeng Li
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, China
- Department of Hepatobiliary Surgery, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Third Hospital of Shanxi Medical University, Tongji Shanxi Hospital, Taiyuan, China
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25
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Wang K, Zhang Y, Si C, Cao Y, Shao P, Zhang P, Wang N, Su G, Qian J, Yang L. Cholesterol: The driving force behind the remodeling of tumor microenvironment in colorectal cancer. Heliyon 2024; 10:e39425. [PMID: 39687190 PMCID: PMC11648115 DOI: 10.1016/j.heliyon.2024.e39425] [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: 08/25/2024] [Revised: 09/24/2024] [Accepted: 10/14/2024] [Indexed: 12/18/2024] Open
Abstract
Essential membrane components and metabolites with a wide range of biological roles are both produced by cholesterol metabolism. Cell-intrinsic and cell-extrinsic stimuli alter cholesterol metabolism in the tumor microenvironment (TME), which in turn encourages colorectal carcinogenesis. Metabolites produced from cholesterol play intricate roles in promoting the development of colorectal cancer (CRC) and stifling immunological responses. By altering the extracellular matrix of the main tumor, redesigning its immunological environment, and altering its mechanical stiffness, cholesterol can encourage the epithelial-mesenchymal transition of the primary tumor, opening up a pathway for tumor metastasis. Its functions in TME remodeling and tumor prevention have been recently identified. In this review we address the function of cholesterol in TME remodeling and therapeutic techniques designed to block cholesterol metabolism, and discuss how combining these strategies with already available anti-CRC medicines can have combined effects and open up new therapeutic avenues.
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Affiliation(s)
- Ke Wang
- Department of Colorectal Surgery, The Affiliated Cancer Hospital of Nanjing Medical University & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Nanjing, China
| | - Yuanyuan Zhang
- Key Laboratory of Drug Quality Control and Pharmacovigilance (Ministry of Education), State Key Laboratory of Natural Medicine, China Pharmaceutical University, Nanjing, China
| | - Chengshuai Si
- Department of Colorectal Surgery, The Affiliated Cancer Hospital of Nanjing Medical University & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Nanjing, China
| | - Yuepeng Cao
- Department of Colorectal Surgery, The Affiliated Cancer Hospital of Nanjing Medical University & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Nanjing, China
| | - Peng Shao
- Department of Colorectal Surgery, The Affiliated Cancer Hospital of Nanjing Medical University & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Nanjing, China
| | - Pei Zhang
- Key Laboratory of Drug Quality Control and Pharmacovigilance (Ministry of Education), State Key Laboratory of Natural Medicine, China Pharmaceutical University, Nanjing, China
| | - Nannan Wang
- Department of Colorectal Surgery, The Affiliated Cancer Hospital of Nanjing Medical University & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Nanjing, China
| | - Guoqing Su
- Department of Colorectal Surgery, The Affiliated Cancer Hospital of Nanjing Medical University & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Nanjing, China
| | - Jinghang Qian
- Department of Colorectal Surgery, The Affiliated Cancer Hospital of Nanjing Medical University & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Nanjing, China
| | - Liu Yang
- Department of Colorectal Surgery, The Affiliated Cancer Hospital of Nanjing Medical University & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Nanjing, China
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26
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Fang L, Gao D, Wang T, Zhao H, Zhang Y, Wang S. From nature to clinic: Quercetin's role in breast cancer immunomodulation. Front Immunol 2024; 15:1483459. [PMID: 39712006 PMCID: PMC11659267 DOI: 10.3389/fimmu.2024.1483459] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2024] [Accepted: 11/19/2024] [Indexed: 12/24/2024] Open
Abstract
Immunotherapy has brought hope to many breast cancer patients, but not all patients benefit from it. Quercetin (Qu), a natural product found in various sources, has anti-inflammatory and anti-tumor properties. We conducted a review of the pharmacological research of Qu in regulating anti-tumor immunity in vivo and in vitro. Qu can directly regulate the local tumor microenvironment (TME) by enhancing the activity of immune cells which includes promoting the infiltration of T cells and natural killer (NK) cells, inhibiting the recruitment of myeloid-derived suppressor cells and tumor-associated macrophages. Additionally, Qu inhibits anaerobic glycolysis in tumor cells, thereby reducing the production and transport of lactic acid. It also suppresses tumor angiogenesis by targeting the vascular endothelial growth factor (VEGF) pathway and the vitamin D pathway. Furthermore, Qu can enhance the efficacy of immunotherapy for breast cancer by modulating the systemic microenvironment. This includes inhibiting obesity-related chronic inflammation to decrease the production of inflammatory factors, regulating the composition of intestinal microbiota, and intervening in the metabolism of intestinal flora. At the same time, we also address challenges in the clinical application of Qu, such as low absorption rates and unknown effective doses. In conclusion, we highlight Qu as a natural immunomodulator that enhances immune cell activity and has the potential to be developed as an adjunct for breast cancer.
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Affiliation(s)
- Liguang Fang
- College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, Shandong, China
| | - Dandan Gao
- The First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan, Shandong, China
| | - Tong Wang
- School of Nursing, Shandong University of Traditional Chinese Medicine, Jinan, Shandong, China
| | - Haijun Zhao
- College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, Shandong, China
- Shandong Co-Innovation Center of Classic Traditional Chinese Medicine (TCM) Formula, Shandong University of Traditional Chinese Medicine, Jinan, Shandong, China
| | - Yanan Zhang
- College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, Shandong, China
| | - Shijun Wang
- College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, Shandong, China
- Shandong Co-Innovation Center of Classic Traditional Chinese Medicine (TCM) Formula, Shandong University of Traditional Chinese Medicine, Jinan, Shandong, China
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27
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Xu Q, Shao D. Leveraging the synergy between anti-angiogenic therapy and immune checkpoint inhibitors to treat digestive system cancers. Front Immunol 2024; 15:1487610. [PMID: 39691707 PMCID: PMC11649667 DOI: 10.3389/fimmu.2024.1487610] [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: 08/28/2024] [Accepted: 11/20/2024] [Indexed: 12/19/2024] Open
Abstract
The response rates to immunotherapy vary widely depending on the type of cancer and the specific treatment used and can be disappointingly low for many solid tumors. Fortunately, due to their complementary mechanisms of action, immunotherapy and anti-angiogenic therapy have synergistic effects in cancer treatment. By normalizing the tumor vasculature, anti-angiogenic therapy can improve blood flow and oxygenation to facilitate better immune cell infiltration into the tumor and enhance the effectiveness of immunotherapy. It also reduces immunosuppressive factors and enhances immune activation, to create a more favorable environment for immune cells to attack the tumor. Their combination leverages the strengths of both therapies to enhance anti-tumor effects and improve patient outcomes. This review discusses the vasculature-immunity crosstalk in the tumor microenvironment and summarizes the latest advances in combining anti-angiogenic therapy and immune checkpoint inhibitors to treat digestive system tumors.
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Affiliation(s)
| | - Dong Shao
- Department of Gastroenterology, The Third Affiliated Hospital of Soochow
University, Changzhou, Jiangsu, China
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28
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Ielpo S, Barberini F, Dabbagh Moghaddam F, Pesce S, Cencioni C, Spallotta F, De Ninno A, Businaro L, Marcenaro E, Bei R, Cifaldi L, Barillari G, Melaiu O. Crosstalk and communication of cancer-associated fibroblasts with natural killer and dendritic cells: New frontiers and unveiled opportunities for cancer immunotherapy. Cancer Treat Rev 2024; 131:102843. [PMID: 39442289 DOI: 10.1016/j.ctrv.2024.102843] [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: 08/27/2024] [Revised: 10/11/2024] [Accepted: 10/13/2024] [Indexed: 10/25/2024]
Abstract
Natural killer (NK) cells and dendritic cells (DCs) are critical mediators of anti-cancer immune responses. In addition to their individual roles, NK cells and DCs are involved in intercellular crosstalk which is essential for the initiation and coordination of adaptive immunity against cancer. However, NK cell and DC activity is often compromised in the tumor microenvironment (TME). Recently, much attention has been paid to one of the major components of the TME, the cancer-associated fibroblasts (CAFs), which not only contribute to extracellular matrix (ECM) deposition and tumor progression but also suppress immune cell functions. It is now well established that CAFs support T cell exclusion from tumor nests and regulate their cytotoxic activity. In contrast, little is currently known about their interaction with NK cells, and DCs. In this review, we describe the interaction of CAFs with NK cells and DCs, by secreting and expressing various mediators in the TME of adult solid tumors. We also provide a detailed overview of ongoing clinical studies evaluating the targeting of stromal factors alone or in combination with immunotherapy based on immune checkpoint inhibitors. Finally, we discuss currently available strategies for the selective depletion of detrimental CAFs and for a better understanding of their interaction with NK cells and DCs.
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Affiliation(s)
- Simone Ielpo
- Department of Clinical Sciences and Translational Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Francesca Barberini
- Department of Clinical Sciences and Translational Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Farnaz Dabbagh Moghaddam
- Institute for Photonics and Nanotechnologies, National Research Council, Via Fosso del Cavaliere, 100, Rome, Italy
| | - Silvia Pesce
- Department of Experimental Medicine and Centre of Excellence for Biomedical Research, University of Genoa, Genoa, Italy; IRCCS Ospedale Policlinico San Martino, Genova, Italy
| | - Chiara Cencioni
- Institute for Systems Analysis and Computer Science "A. Ruberti", National Research Council (IASI-CNR), Rome, Italy
| | - Francesco Spallotta
- Department of Biology and Biotechnologies Charles Darwin, Sapienza University, 00185, Rome, Italy; Pasteur Institute Italy-Fondazione Cenci Bolognetti, Italy
| | - Adele De Ninno
- Institute for Photonics and Nanotechnologies, National Research Council, Via Fosso del Cavaliere, 100, Rome, Italy
| | - Luca Businaro
- Institute for Photonics and Nanotechnologies, National Research Council, Via Fosso del Cavaliere, 100, Rome, Italy
| | - Emanuela Marcenaro
- Department of Experimental Medicine and Centre of Excellence for Biomedical Research, University of Genoa, Genoa, Italy; IRCCS Ospedale Policlinico San Martino, Genova, Italy
| | - Roberto Bei
- Department of Clinical Sciences and Translational Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Loredana Cifaldi
- Department of Clinical Sciences and Translational Medicine, University of Rome Tor Vergata, Rome, Italy.
| | - Giovanni Barillari
- Department of Clinical Sciences and Translational Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Ombretta Melaiu
- Department of Clinical Sciences and Translational Medicine, University of Rome Tor Vergata, Rome, Italy.
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Masuda C, Onishi S, Yorozu K, Kurasawa M, Morinaga M, Wakita D, Sugimoto M. PD-L1 and VEGF dual blockade enhances anti-tumor effect on brain metastasis in hematogenous metastasis model. Clin Exp Metastasis 2024; 41:909-924. [PMID: 39231916 PMCID: PMC11607052 DOI: 10.1007/s10585-024-10309-y] [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: 03/26/2024] [Accepted: 08/20/2024] [Indexed: 09/06/2024]
Abstract
Immunotherapy improves survival outcomes in cancer patients, but there is still an unmet clinical need in the treatment of brain metastases. Here, we used a mouse model to investigate the antitumor effect of programmed death-ligand 1 (PD-L1) and vascular endothelial growth factor (VEGF) dual blockade on metastatic brain tumors and evaluated immune responses during treatment. After establishing hematogenous brain metastasis by transplanting murine bladder carcinoma MBT2 cells stably expressing secNLuc reporter via the internal carotid artery of C3H/HeNCrl mice, we observed the formation of metastases not only in the brain parenchyma but also in the ventricles. The observed pathological areas showed that metastases in the ventricle were histologically larger than that in the brain parenchyma. Regarding the total tumor burden in the whole brain as revealed by Nluc activities, the combination of anti-PD-L1 antibody and anti-VEGF antibody showed a stronger anti-tumor effect than each single agent. Anti-PD-L1 antibody alone enhanced CD8+ T cell priming in regional lymph nodes, increased the proportion of activated CD8+ T cells in whole brain, and increased the density of CD8+ cells in the brain parenchyma. Furthermore, anti-VEGF antibody alone decreased microvessel density (MVD) in ventricular metastases, and the combination treatment increased intratumoral CD8+ cell density in the brain parenchyma and ventricular metastases. These results suggest that PD-L1 blockade enhanced cancer immunity not only in brain metastases lesions but also in the regional lymph nodes of the metastases, and that the addition of VEGF blockade increased the antitumor effect by increasing the infiltration of activated CD8+ T cell and decreasing MVD.
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Affiliation(s)
- Chinami Masuda
- Product Research Department, Chugai Pharmaceutical Co., Ltd., Chugai Life Science Park Yokohama, 216, Totsuka-Cho, Totsuka-Ku, Yokohama, Kanagawa, 244-8602, Japan.
| | - Shinichi Onishi
- Product Research Department, Chugai Pharmaceutical Co., Ltd., Chugai Life Science Park Yokohama, 216, Totsuka-Cho, Totsuka-Ku, Yokohama, Kanagawa, 244-8602, Japan
| | - Keigo Yorozu
- Product Research Department, Chugai Pharmaceutical Co., Ltd., Chugai Life Science Park Yokohama, 216, Totsuka-Cho, Totsuka-Ku, Yokohama, Kanagawa, 244-8602, Japan
| | - Mitsue Kurasawa
- Product Research Department, Chugai Pharmaceutical Co., Ltd., Chugai Life Science Park Yokohama, 216, Totsuka-Cho, Totsuka-Ku, Yokohama, Kanagawa, 244-8602, Japan
| | - Mamiko Morinaga
- Product Research Department, Chugai Pharmaceutical Co., Ltd., Chugai Life Science Park Yokohama, 216, Totsuka-Cho, Totsuka-Ku, Yokohama, Kanagawa, 244-8602, Japan
| | - Daiko Wakita
- Product Research Department, Chugai Pharmaceutical Co., Ltd., Chugai Life Science Park Yokohama, 216, Totsuka-Cho, Totsuka-Ku, Yokohama, Kanagawa, 244-8602, Japan
| | - Masamichi Sugimoto
- Product Research Department, Chugai Pharmaceutical Co., Ltd., Chugai Life Science Park Yokohama, 216, Totsuka-Cho, Totsuka-Ku, Yokohama, Kanagawa, 244-8602, Japan
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30
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Li X, Li R, Miao X, Zhou X, Wu B, Cao J, Wang C, Li S, Cai J. Integrated Single Cell Analysis Reveals An Atlas of Tumor Associated Macrophages in Hepatocellular Carcinoma. Inflammation 2024; 47:2077-2093. [PMID: 38668836 DOI: 10.1007/s10753-024-02026-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2023] [Revised: 04/03/2024] [Accepted: 04/12/2024] [Indexed: 11/30/2024]
Abstract
Hepatocellular carcinoma (HCC), one of the most prevalent cancers globally, is closely associated with tumor-associated macrophages (TAMs), including monocyte-derived macrophages and liver-resident Kupffer cells. Understanding TAM heterogeneity at the cellular level is crucial for developing effective HCC prevention and treatment strategies. In this study, we conducted an integrated single-cell analysis of four cohorts (GSE140228, GSE125449, GSE149614 and GSE156625) to elucidate the TAM landscape in HCC. We identified 284 gene markers, termed Panmyeloid markers, that characterize myeloid cells within this context. Our analysis distinguished six clusters of monocyte-derived macrophages (Macro1-Macro6) and four clusters of Kupffer cells (Kupffer1-Kupffer4). Notably, CXCL10 + macrophages and MT1G + Kupffer cells, predominantly located within tumor tissues, exhibited distinct functional characteristics relevant to HCC. We also explored cellular communication between TAMs and T cells, uncovering potential signaling pathways such as the CXCL10/CXCL11-CXCR3 and CXCL12-CXCR4 networks. These findings enhance our understanding of TAMs in HCC and open new avenues for targeted therapeutic interventions.
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Affiliation(s)
- Xinqiang Li
- Organ Transplantation Center, Affiliated Hospital of Qingdao University, Qingdao, China
- Institute of Organ Donation and Transplantation, Medical College of Qingdao University, Qingdao, China
| | - Ruixia Li
- Department of Pulmonary and Critical Care Medicine, Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Xiaolong Miao
- Organ Transplantation Center, Affiliated Hospital of Qingdao University, Qingdao, China
- Institute of Organ Donation and Transplantation, Medical College of Qingdao University, Qingdao, China
| | - Xin Zhou
- Organ Transplantation Center, Affiliated Hospital of Qingdao University, Qingdao, China
- Institute of Organ Donation and Transplantation, Medical College of Qingdao University, Qingdao, China
| | - Bin Wu
- Organ Transplantation Center, Affiliated Hospital of Qingdao University, Qingdao, China
- Institute of Organ Donation and Transplantation, Medical College of Qingdao University, Qingdao, China
| | - Junning Cao
- Organ Transplantation Center, Affiliated Hospital of Qingdao University, Qingdao, China
- Institute of Organ Donation and Transplantation, Medical College of Qingdao University, Qingdao, China
| | - Chengyu Wang
- Organ Transplantation Center, Affiliated Hospital of Qingdao University, Qingdao, China
- Institute of Organ Donation and Transplantation, Medical College of Qingdao University, Qingdao, China
| | - Shipeng Li
- Department of Hepatopancreaticobiliary Surgery, Henan Provincial People's Hospital, Zhengzhou University, Zhengzhou, China.
| | - Jinzhen Cai
- Organ Transplantation Center, Affiliated Hospital of Qingdao University, Qingdao, China.
- Institute of Organ Donation and Transplantation, Medical College of Qingdao University, Qingdao, China.
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31
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Chap BS, Rayroux N, Grimm AJ, Ghisoni E, Dangaj Laniti D. Crosstalk of T cells within the ovarian cancer microenvironment. Trends Cancer 2024; 10:1116-1130. [PMID: 39341696 DOI: 10.1016/j.trecan.2024.09.001] [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: 06/28/2024] [Revised: 09/02/2024] [Accepted: 09/03/2024] [Indexed: 10/01/2024]
Abstract
Ovarian cancer (OC) represents ecosystems of highly diverse tumor microenvironments (TMEs). The presence of tumor-infiltrating lymphocytes (TILs) is linked to enhanced immune responses and long-term survival. In this review we present emerging evidence suggesting that cellular crosstalk tightly regulates the distribution of TILs within the TME, underscoring the need to better understand key cellular networks that promote or impede T cell infiltration in OC. We also capture the emergent methodologies and computational techniques that enable the dissection of cell-cell crosstalk. Finally, we present innovative ex vivo TME models that can be leveraged to map and perturb cellular communications to enhance T cell infiltration and immune reactivity.
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Affiliation(s)
- Bovannak S Chap
- Department of Oncology, Lausanne University Hospital, University of Lausanne, Lausanne, Switzerland; Ludwig Institute for Cancer Research, Lausanne Branch, University of Lausanne (UNIL), Lausanne, Switzerland; Agora Cancer Research Center, Lausanne, Switzerland
| | - Nicolas Rayroux
- Department of Oncology, Lausanne University Hospital, University of Lausanne, Lausanne, Switzerland; Ludwig Institute for Cancer Research, Lausanne Branch, University of Lausanne (UNIL), Lausanne, Switzerland; Agora Cancer Research Center, Lausanne, Switzerland
| | - Alizée J Grimm
- Department of Oncology, Lausanne University Hospital, University of Lausanne, Lausanne, Switzerland; Ludwig Institute for Cancer Research, Lausanne Branch, University of Lausanne (UNIL), Lausanne, Switzerland; Agora Cancer Research Center, Lausanne, Switzerland
| | - Eleonora Ghisoni
- Department of Oncology, Lausanne University Hospital, University of Lausanne, Lausanne, Switzerland; Ludwig Institute for Cancer Research, Lausanne Branch, University of Lausanne (UNIL), Lausanne, Switzerland; Agora Cancer Research Center, Lausanne, Switzerland
| | - Denarda Dangaj Laniti
- Department of Oncology, Lausanne University Hospital, University of Lausanne, Lausanne, Switzerland; Ludwig Institute for Cancer Research, Lausanne Branch, University of Lausanne (UNIL), Lausanne, Switzerland; Agora Cancer Research Center, Lausanne, Switzerland.
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32
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Qi MH, Li JT, Zhai B. Mechanisms of vascular co-option as a potential therapeutic target in hepatocellular carcinoma. Shijie Huaren Xiaohua Zazhi 2024; 32:827-834. [DOI: 10.11569/wcjd.v32.i11.827] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2024] [Revised: 09/24/2024] [Accepted: 10/30/2024] [Indexed: 11/28/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common cancers, which has an insidious onset, and most of the patients have already lost the chance of radical surgery at the time of the first diagnosis, so systematic antitumor therapy has become the key to the treatment of intermediate and advanced HCC. The emergence of drug resistance to antitumor drugs is one of the most important reasons for the poor efficacy, which affects the prognosis of HCC patients, and how to improve the therapeutic efficacy for HCC is still the main focus of the present research. Although the research on antitumor drugs based on neovascularization has been deepening both domestically and abroad, less research has been done on the vascular co-option mode, which shares blood vessels of normal tissues to meet the metabolic needs of the tumor itself, and its impact on the progression of HCC and antitumor therapy has not been extensively studied. In this paper, we provide an overview of the impact of vascular co-option on multiple treatment modalities for hepatocellular carcinoma and related mechanisms, with a view to laying a theoretical foundation for improving drug resistance in HCC.
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Affiliation(s)
- Ming-Hao Qi
- Department of General Surgery, The Fourth Affiliated Hospital of Harbin Medical University, Harbin 150000, Heilongjiang Province, China
| | - Jing-Tao Li
- Department of General Surgery, The Fourth Affiliated Hospital of Harbin Medical University, Harbin 150000, Heilongjiang Province, China
| | - Bo Zhai
- Department of General Surgery, The Fourth Affiliated Hospital of Harbin Medical University, Harbin 150000, Heilongjiang Province, China
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Pan D, Liu J, Huang X, Wang S, Kuerban K, Yan Y, Zhu YZ, Ye L. Challenges and New Directions in Therapeutic Cancer Vaccine Development. Vaccines (Basel) 2024; 12:1341. [PMID: 39772003 PMCID: PMC11679661 DOI: 10.3390/vaccines12121341] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2024] [Revised: 11/12/2024] [Accepted: 11/15/2024] [Indexed: 01/11/2025] Open
Abstract
Tumor vaccine is a promising immunotherapy for solid tumors. Therapeutic tumor vaccines aim at inducing tumor regression, establishing durable antitumor memory, and avoiding non-specific or adverse reactions. However, tumor-induced immune suppression and immune resistance pose challenges to achieving this goal. In this article, we review multiple challenges currently faced in the development of therapeutic tumor vaccines, with a particular focus on anonymous antigen vaccines in situ as a new direction. We summarize the research progress in this area, aiming to provide a reference for future studies on tumor vaccines.
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Affiliation(s)
- Danjie Pan
- Laboratory of Drug Discovery from Natural Resources and Industrialization, School of Pharmacy, Macau University of Science and Technology, Macau 999078, China; (D.P.)
- Department of Biological Medicines, School of Pharmacy, Fudan University, Shanghai 201203, China; (J.L.)
| | - Jiayang Liu
- Department of Biological Medicines, School of Pharmacy, Fudan University, Shanghai 201203, China; (J.L.)
| | - Xuan Huang
- Department of Biological Medicines, School of Pharmacy, Fudan University, Shanghai 201203, China; (J.L.)
| | - Songna Wang
- Laboratory of Drug Discovery from Natural Resources and Industrialization, School of Pharmacy, Macau University of Science and Technology, Macau 999078, China; (D.P.)
| | - Kudelaidi Kuerban
- Department of Biological Medicines, School of Pharmacy, Fudan University, Shanghai 201203, China; (J.L.)
| | - Yan Yan
- Laboratory of Drug Discovery from Natural Resources and Industrialization, School of Pharmacy, Macau University of Science and Technology, Macau 999078, China; (D.P.)
| | - Yi Zhun Zhu
- Laboratory of Drug Discovery from Natural Resources and Industrialization, School of Pharmacy, Macau University of Science and Technology, Macau 999078, China; (D.P.)
| | - Li Ye
- Laboratory of Drug Discovery from Natural Resources and Industrialization, School of Pharmacy, Macau University of Science and Technology, Macau 999078, China; (D.P.)
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Ghisoni E, Morotti M, Sarivalasis A, Grimm AJ, Kandalaft L, Laniti DD, Coukos G. Immunotherapy for ovarian cancer: towards a tailored immunophenotype-based approach. Nat Rev Clin Oncol 2024; 21:801-817. [PMID: 39232212 DOI: 10.1038/s41571-024-00937-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/12/2024] [Indexed: 09/06/2024]
Abstract
Despite documented evidence that ovarian cancer cells express immune-checkpoint molecules, such as PD-1 and PD-L1, and of a positive correlation between the presence of tumour-infiltrating lymphocytes and favourable overall survival outcomes in patients with this tumour type, the results of trials testing immune-checkpoint inhibitors (ICIs) in these patients thus far have been disappointing. The lack of response to ICIs can be attributed to tumour heterogeneity as well as inherent or acquired resistance associated with the tumour microenvironment (TME). Understanding tumour immunobiology, discovering biomarkers for patient selection and establishing optimal treatment combinations remains the hope but also a key challenge for the future application of immunotherapy in ovarian cancer. In this Review, we summarize results from trials testing ICIs in patients with ovarian cancer. We propose the implementation of a systematic CD8+ T cell-based immunophenotypic classification of this malignancy, followed by discussions of the preclinical data providing the basis to treat such immunophenotypes with combination immunotherapies. We posit that the integration of an accurate TME immunophenotype characterization with genetic data can enable the design of tailored therapeutic approaches and improve patient recruitment in clinical trials. Lastly, we propose a roadmap incorporating tissue-based profiling to guide future trials testing adoptive cell therapy approaches and assess novel immunotherapy combinations while promoting collaborative research.
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Affiliation(s)
- Eleonora Ghisoni
- Department of Oncology, Lausanne University Hospital, University of Lausanne, Lausanne, Switzerland
- Ludwig Institute for Cancer Research, Lausanne Branch, University of Lausanne (UNIL), Lausanne, Switzerland
- Agora Cancer Research Center, Lausanne, Switzerland
| | - Matteo Morotti
- Department of Oncology, Lausanne University Hospital, University of Lausanne, Lausanne, Switzerland
- Ludwig Institute for Cancer Research, Lausanne Branch, University of Lausanne (UNIL), Lausanne, Switzerland
- Agora Cancer Research Center, Lausanne, Switzerland
| | - Apostolos Sarivalasis
- Department of Oncology, Lausanne University Hospital, University of Lausanne, Lausanne, Switzerland
| | - Alizée J Grimm
- Department of Oncology, Lausanne University Hospital, University of Lausanne, Lausanne, Switzerland
- Ludwig Institute for Cancer Research, Lausanne Branch, University of Lausanne (UNIL), Lausanne, Switzerland
- Agora Cancer Research Center, Lausanne, Switzerland
| | - Lana Kandalaft
- Ludwig Institute for Cancer Research, Lausanne Branch, University of Lausanne (UNIL), Lausanne, Switzerland
- Center of Experimental Therapeutics, Department of Oncology, Lausanne University Hospital, Lausanne, Switzerland
| | - Denarda Dangaj Laniti
- Department of Oncology, Lausanne University Hospital, University of Lausanne, Lausanne, Switzerland
- Ludwig Institute for Cancer Research, Lausanne Branch, University of Lausanne (UNIL), Lausanne, Switzerland
- Agora Cancer Research Center, Lausanne, Switzerland
| | - George Coukos
- Department of Oncology, Lausanne University Hospital, University of Lausanne, Lausanne, Switzerland.
- Ludwig Institute for Cancer Research, Lausanne Branch, University of Lausanne (UNIL), Lausanne, Switzerland.
- Agora Cancer Research Center, Lausanne, Switzerland.
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Huang AY, Burke KP, Porter R, Meiger L, Fatouros P, Yang J, Robitschek E, Vokes N, Ricker C, Rosado V, Tarantino G, Chen J, Aprati TJ, Glettig MC, He Y, Wang C, Fu D, Ho LL, Galani K, Freeman GJ, Buchbinder EI, Stephen Hodi F, Kellis M, Boland GM, Sharpe AH, Liu D. Stratified analysis identifies HIF-2 α as a therapeutic target for highly immune-infiltrated melanomas. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.10.29.620300. [PMID: 39554029 PMCID: PMC11565796 DOI: 10.1101/2024.10.29.620300] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 11/19/2024]
Abstract
While immune-checkpoint blockade (ICB) has revolutionized treatment of metastatic melanoma over the last decade, the identification of broadly applicable robust biomarkers has been challenging, driven in large part by the heterogeneity of ICB regimens and patient and tumor characteristics. To disentangle these features, we performed a standardized meta-analysis of eight cohorts of patients treated with anti-PD-1 (n=290), anti-CTLA-4 (n=175), and combination anti-PD-1/anti-CTLA-4 (n=51) with RNA sequencing of pre-treatment tumor and clinical annotations. Stratifying by immune-high vs -low tumors, we found that surprisingly, high immune infiltrate was a biomarker for response to combination ICB, but not anti-PD-1 alone. Additionally, hypoxia-related signatures were associated with non-response to anti-PD-1, but only amongst immune infiltrate-high melanomas. In a cohort of scRNA-seq of patients with metastatic melanoma, hypoxia also correlated with immunosuppression and changes in tumor-stromal communication in the tumor microenvironment (TME). Clinically actionable targets of hypoxia signaling were also uniquely expressed across different cell types. We focused on one such target, HIF-2α, which was specifically upregulated in endothelial cells and fibroblasts but not in immune cells or tumor cells. HIF-2α inhibition, in combination with anti-PD-1, enhanced tumor growth control in pre-clinical models, but only in a more immune-infiltrated melanoma model. Our work demonstrates how careful stratification by clinical and molecular characteristics can be leveraged to derive meaningful biological insights and lead to the rational discovery of novel clinical targets for combination therapy.
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Affiliation(s)
- Amy Y Huang
- Dana-Farber Cancer Institute, Boston, MA, USA
- Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA
- Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA
- Gene Lay Institute of Immunology and Inflammation, Brigham and Women's Hospital, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
- Massachusetts Institute of Technology, Cambridge, USA
| | - Kelly P Burke
- Dana-Farber Cancer Institute, Boston, MA, USA
- Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA
- Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA
- Gene Lay Institute of Immunology and Inflammation, Brigham and Women's Hospital, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Ryan Porter
- Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA
- Gene Lay Institute of Immunology and Inflammation, Brigham and Women's Hospital, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Lynn Meiger
- Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA
- Gene Lay Institute of Immunology and Inflammation, Brigham and Women's Hospital, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Peter Fatouros
- Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA
- Gene Lay Institute of Immunology and Inflammation, Brigham and Women's Hospital, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Jiekun Yang
- Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA
- Massachusetts Institute of Technology, Cambridge, USA
- Rutgers University, New Brunswick, NJ, USA
| | - Emily Robitschek
- Dana-Farber Cancer Institute, Boston, MA, USA
- Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Natalie Vokes
- University of Texas MD Anderson Cancer Center, Houston, USA
| | - Cora Ricker
- Dana-Farber Cancer Institute, Boston, MA, USA
- Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Valeria Rosado
- Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA
- Gene Lay Institute of Immunology and Inflammation, Brigham and Women's Hospital, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Giuseppe Tarantino
- Dana-Farber Cancer Institute, Boston, MA, USA
- Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA
- Harvard Medical School, Boston, MA, USA
| | - Jiajia Chen
- Dana-Farber Cancer Institute, Boston, MA, USA
- Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Tyler J Aprati
- Dana-Farber Cancer Institute, Boston, MA, USA
- Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Marc C Glettig
- Dana-Farber Cancer Institute, Boston, MA, USA
- Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA
- ETH Zürich, Zurich, Switzerland
| | - Yiwen He
- Dana-Farber Cancer Institute, Boston, MA, USA
- Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Cassia Wang
- Massachusetts Institute of Technology, Cambridge, USA
| | - Doris Fu
- Massachusetts Institute of Technology, Cambridge, USA
| | - Li-Lun Ho
- Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA
- Massachusetts Institute of Technology, Cambridge, USA
| | - Kyriakitsa Galani
- Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA
- Massachusetts Institute of Technology, Cambridge, USA
| | - Gordon J Freeman
- Dana-Farber Cancer Institute, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
| | | | - F Stephen Hodi
- Dana-Farber Cancer Institute, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
| | - Manolis Kellis
- Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA
- Massachusetts Institute of Technology, Cambridge, USA
| | - Genevieve M Boland
- Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA
- Harvard Medical School, Boston, MA, USA
- Massachusetts General Hospital, Boston, MA, USA
| | - Arlene H Sharpe
- Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA
- Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA
- Gene Lay Institute of Immunology and Inflammation, Brigham and Women's Hospital, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - David Liu
- Dana-Farber Cancer Institute, Boston, MA, USA
- Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA
- Harvard Medical School, Boston, MA, USA
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Cao Y, Yi Y, Han C, Shi B. NF-κB signaling pathway in tumor microenvironment. Front Immunol 2024; 15:1476030. [PMID: 39493763 PMCID: PMC11530992 DOI: 10.3389/fimmu.2024.1476030] [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: 08/05/2024] [Accepted: 09/30/2024] [Indexed: 11/05/2024] Open
Abstract
The genesis and progression of tumors are multifaceted processes influenced by genetic mutations within the tumor cells and the dynamic interplay with their surrounding milieu, which incessantly impacts the course of cancer. The tumor microenvironment (TME) is a complex and dynamic entity that encompasses not only the tumor cells but also an array of non-cancerous cells, signaling molecules, and the extracellular matrix. This intricate network is crucial in tumor progression, metastasis, and response to treatments. The TME is populated by diverse cell types, including immune cells, fibroblasts, endothelial cells, alongside cytokines and growth factors, all of which play roles in either suppressing or fostering tumor growth. Grasping the nuances of the interactions within the TME is vital for the advancement of targeted cancer therapies. Consequently, a thorough understanding of the alterations of TME and the identification of upstream regulatory targets have emerged as a research priority. NF-κB transcription factors, central to inflammation and innate immunity, are increasingly recognized for their significant role in cancer onset and progression. This review emphasizes the crucial influence of the NF-κB signaling pathway within the TME, underscoring its roles in the development and advancement of cancer. By examining the interactions between NF-κB and various components of the TME, targeting the NF-κB pathway appears as a promising cancer treatment approach.
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Affiliation(s)
- Yaning Cao
- Department of Blood Transfusion, Changzhou Hospital of Traditional Chinese Medicine, Changzhou, Jiangsu, China
| | - Yanan Yi
- Department of Laboratory Medicine, Northern Jiangsu People’s Hospital Affiliated to Yangzhou University, Yangzhou, Jiangsu, China
| | - Chongxu Han
- Department of Laboratory Medicine, Northern Jiangsu People’s Hospital Affiliated to Yangzhou University, Yangzhou, Jiangsu, China
| | - Bingwei Shi
- Department of Blood Transfusion, Changzhou Hospital of Traditional Chinese Medicine, Changzhou, Jiangsu, China
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37
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Zhang Y, Wang X, Mou Y, Wang Y, Liu W, Feng W, Chen R, Zhang M, Sun J. Traditional Chinese medicine in the treatment of lung pre-metastatic niche: Efficacies and mechanisms. Heliyon 2024; 10:e38431. [PMID: 39398007 PMCID: PMC11470612 DOI: 10.1016/j.heliyon.2024.e38431] [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: 06/26/2024] [Revised: 09/21/2024] [Accepted: 09/24/2024] [Indexed: 10/15/2024] Open
Abstract
Metastasis is the main cause of death in cancer patients, the lung is one of the most common metastatic organs of malignant solid tumors. Before tumor cells metastasize to the lungs, they interact with immunosuppressive cells, alveolar epithelial cells, and lung fibroblasts to form a pre-metastatic niche. The pre-metastatic niche is a key factor leading to tumor cell metastasis to the lungs. Research has found that traditional Chinese medicine and its components can inhibit the formation of pre-metastatic niche. Therefore, this article reviewed the research progress on the formation of lung pre-metastatic niche and the intervention of traditional Chinese medicine in pulmonary PMN, in order to provide new Chinese medicine prescriptions and research ideas for further clinical prevention and treatment of tumor metastasis to the lung.
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Affiliation(s)
- YaNan Zhang
- College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, Shandong Province, 250355, China
| | - XiaoYan Wang
- College of Acupuncture and Tuina, Shandong University of Traditional Chinese Medicine, Jinan, Shandong Province, 250355, China
| | - Yue Mou
- College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, Shandong Province, 250355, China
| | - YingZheng Wang
- College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, Shandong Province, 250355, China
| | - WeiDong Liu
- College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, Shandong Province, 250355, China
| | - WeiKe Feng
- College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, Shandong Province, 250355, China
| | - Rong Chen
- College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, Shandong Province, 250355, China
| | - MeiZhi Zhang
- College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, Shandong Province, 250355, China
| | - Jing Sun
- College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, Shandong Province, 250355, China
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Ding S, Zhang X, Wang G, Shi J, Zhu J, Yan J, Wang J, Wu J. Promoting diabetic oral mucosa wound healing with a light-responsive hydrogel adaptive to the microenvironment. Heliyon 2024; 10:e38599. [PMID: 39435107 PMCID: PMC11492349 DOI: 10.1016/j.heliyon.2024.e38599] [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: 06/12/2024] [Revised: 09/24/2024] [Accepted: 09/26/2024] [Indexed: 10/23/2024] Open
Abstract
In diabetic patients, compromised angiogenesis due to endothelial dysfunction leads to delayed intraoral wound healing. However, the moist and dynamic environment of the oral cavity impedes the use of normal wound dressings. Sulfated chitosan (SCS) is a promising biomaterial that promoting angiogenesis. Here, a light-responsive hydrogel combined with SCS explored intraoral wound healing. We designed a SCS-modified hydrogel combined with alginate Methacryloyl (AlgMA) and acrylamide (AM) and demonstrated efficient wet adhesion and mechanical properties suitable for the wet and dynamic oral environment. In vitro, the SAA hydrogel improved the tube formation of human umbilical vein endothelial cells (HUVECs) under high-glucose conditions. Further investigations revealed that the SAA hydrogel can regulate HUVEC-macrophage interactions, leading to a shift in macrophage polarization from M1 to M2, thereby fostering an environment conducive to angiogenesis under high-glucose condition. The results demonstrated the substantial therapeutic impact of the SAA hydrogel on diabetic oral defect repair by effectively enhancing the local blood supply and angiogenesis.
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Affiliation(s)
- Shuwen Ding
- Department of Prosthodontics, Stomatological Hospital and Dental School of Tongji University, Shanghai Engineering Research Center of Tooth Restoration and Regeneration, Shanghai, PR China
| | - Xiaohui Zhang
- State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, 200237, PR China
- Engineering Research Center for Biomedical Materials of Ministry of Education, East China University of Science and Technology, Shanghai, 200237, PR China
| | - Gaopeng Wang
- State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, 200237, PR China
- Engineering Research Center for Biomedical Materials of Ministry of Education, East China University of Science and Technology, Shanghai, 200237, PR China
| | - Jiaying Shi
- Department of Prosthodontics, Stomatological Hospital and Dental School of Tongji University, Shanghai Engineering Research Center of Tooth Restoration and Regeneration, Shanghai, PR China
| | - Jiayu Zhu
- Department of Prosthodontics, Stomatological Hospital and Dental School of Tongji University, Shanghai Engineering Research Center of Tooth Restoration and Regeneration, Shanghai, PR China
| | - Jiayu Yan
- Department of Prosthodontics, Stomatological Hospital and Dental School of Tongji University, Shanghai Engineering Research Center of Tooth Restoration and Regeneration, Shanghai, PR China
| | - Jing Wang
- State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, 200237, PR China
- Engineering Research Center for Biomedical Materials of Ministry of Education, East China University of Science and Technology, Shanghai, 200237, PR China
| | - Junhua Wu
- Department of Prosthodontics, Stomatological Hospital and Dental School of Tongji University, Shanghai Engineering Research Center of Tooth Restoration and Regeneration, Shanghai, PR China
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39
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Shin S, Kim CH, Son S, Lee JA, Kwon S, You DG, Lee J, Kim J, Jo DG, Ko H, Park JH. PEDF-Enriched Extracellular Vesicle for Vessel Normalization to Potentiate Immune Checkpoint Blockade Therapy. Biomater Res 2024; 28:0068. [PMID: 39355307 PMCID: PMC11443973 DOI: 10.34133/bmr.0068] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2024] [Accepted: 07/29/2024] [Indexed: 10/03/2024] Open
Abstract
The abnormal tumor vasculature acts as the physical and functional barrier to the infiltration and activity of effector T cells, leading to the low response rate of immune checkpoint inhibitors (ICIs). Herein, antiangiogenic extracellular vesicles that enable normalization of the tumor-associated vasculature were prepared to potentiate the efficacy of ICIs. Small extracellular vesicles were exploited as the delivery platform to protect the antiangiogenic protein, pigment epithelium-derived factor (PEDF), from proteolytic degradation. Along with the physicochemical characteristics of the PEDF-enriched extracellular vesicles (P-EVs), their inhibitory effects on migration, proliferation, and tube formation of endothelial cells were investigated in vitro. In tumor-bearing mice, it was confirmed that, compared to bare PEDFs, P-EVs efficiently reduced vessel leakiness, improved blood perfusion, and attenuated hypoxia. Consequently, when combined with anti-PD-1 antibodies, P-EVs remarkably augmented the antitumor immunity, as evidenced by increased infiltration of CD8+ T cells and reduced regulatory T cells. These results suggest that P-EVs are promising therapeutics for tumors refractory to ICIs.
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Affiliation(s)
- Sol Shin
- Department of Health Sciences and Technology, SAIHST,
Sungkyunkwan University, Seoul 06355, Republic of Korea
- School of Chemical Engineering, College of Engineering,
Sungkyunkwan University, Suwon 16419, Republic of Korea
| | - Chan Ho Kim
- School of Chemical Engineering, College of Engineering,
Sungkyunkwan University, Suwon 16419, Republic of Korea
| | - Soyoung Son
- Department of Health Sciences and Technology, SAIHST,
Sungkyunkwan University, Seoul 06355, Republic of Korea
- School of Chemical Engineering, College of Engineering,
Sungkyunkwan University, Suwon 16419, Republic of Korea
| | - Jae Ah Lee
- School of Chemical Engineering, College of Engineering,
Sungkyunkwan University, Suwon 16419, Republic of Korea
| | - Seunglee Kwon
- School of Chemical Engineering, College of Engineering,
Sungkyunkwan University, Suwon 16419, Republic of Korea
| | - Dong Gil You
- Massachusetts General Hospital,
Harvard Medical School, Boston, MA, USA
| | - Jungmi Lee
- School of Chemical Engineering, College of Engineering,
Sungkyunkwan University, Suwon 16419, Republic of Korea
| | - Jeongyun Kim
- Department of Health Sciences and Technology, SAIHST,
Sungkyunkwan University, Seoul 06355, Republic of Korea
| | - Dong-Gyu Jo
- Biomedical Institute for Convergence at SKKU (BICS),
Sungkyunkwan University, Suwon 16419, Republic of Korea
- School of Pharmacy,
Sungkyunkwan University, Suwon, Republic of Korea
- ExoStemTech Inc., 55 Hanyangdaehak-ro, Sangnok-gu, Ansan 15588, Republic of Korea
| | - Hyewon Ko
- School of Pharmacy,
Sungkyunkwan University, Suwon, Republic of Korea
- Bionanotechnology Research Center,
Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Republic of Korea
| | - Jae Hyung Park
- Department of Health Sciences and Technology, SAIHST,
Sungkyunkwan University, Seoul 06355, Republic of Korea
- School of Chemical Engineering, College of Engineering,
Sungkyunkwan University, Suwon 16419, Republic of Korea
- Biomedical Institute for Convergence at SKKU (BICS),
Sungkyunkwan University, Suwon 16419, Republic of Korea
- ExoStemTech Inc., 55 Hanyangdaehak-ro, Sangnok-gu, Ansan 15588, Republic of Korea
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40
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Mao S, Wang Y, Chao N, Zeng L, Zhang L. Integrated analysis of single-cell RNA-seq and bulk RNA-seq reveals immune suppression subtypes and establishes a novel signature for determining the prognosis in lung adenocarcinoma. Cell Oncol (Dordr) 2024; 47:1697-1713. [PMID: 38616208 DOI: 10.1007/s13402-024-00948-4] [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] [Accepted: 04/07/2024] [Indexed: 04/16/2024] Open
Abstract
BACKGROUND Lung adenocarcinoma (LUAD) is the most common histological type of lung cancer with lower survival rates. Recent advancements in targeted therapies and immunotherapies targeting immune checkpoints have achieved remarkable success, there is still a large percentage of LUAD that lacks available therapeutic options. Due to tumor heterogeneity, the diagnosis and treatment of LUAD are challenging. Exploring the biology of LUAD and identifying new biomarker and therapeutic targets options are essential. METHOD We performed single-cell RNA sequencing (scRNA-seq) of 6 paired primary and adjacent LUAD tissues, and integrative omics analysis of the scRNA-seq, bulk RNA-seq and whole-exome sequencing data revealed molecular subtype characteristics. Our experimental results confirm that CDC25C gene can serve as a potential marker for poor prognosis in LUAD. RESULTS We investigated aberrant gene expression in diverse cell types in LUAD via the scRNA-seq data. Moreover, multi-omics clustering revealed four subgroups defined by transcriptional profile and molecular subtype 4 (MS4) with poor survival probability, and immune cell infiltration signatures revealed that MS4 tended to be the immunosuppressive subtype. Our study revealed that the CDC25C gene can be a distinct prognostic biomarker that indicates immune infiltration levels and response to immunotherapy in LUAD patients. Our experimental results concluded that CDC25C expression affects lung cancer cell invasion and migration, might play a key role in regulating Epithelial-Mesenchymal Transition (EMT) pathways. CONCLUSIONS Our multi-omics result revealed a comprehensive set of molecular attributes associated with prognosis-related genes in LUAD at the cellular and tissue level. Identification of a subtype of immunosuppressive TME and prognostic signature for LUAD. We identified the cell cycle regulation gene CDC25C affects lung cancer cell invasion and migration, which can be used as a potential biomarker for LUAD.
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Affiliation(s)
- Shengqiang Mao
- Department of Respiratory and Critical Care Medicine, Frontiers Science Center for Disease-related Molecular Network, Center of Precision Medicine, Precision Medicine Key Laboratory of Sichuan Province, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Yilong Wang
- Department of Respiratory and Critical Care Medicine, Frontiers Science Center for Disease-related Molecular Network, Center of Precision Medicine, Precision Medicine Key Laboratory of Sichuan Province, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Ningning Chao
- Department of Respiratory and Critical Care Medicine, Frontiers Science Center for Disease-related Molecular Network, Center of Precision Medicine, Precision Medicine Key Laboratory of Sichuan Province, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Lingyan Zeng
- Department of Respiratory and Critical Care Medicine, Frontiers Science Center for Disease-related Molecular Network, Center of Precision Medicine, Precision Medicine Key Laboratory of Sichuan Province, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Li Zhang
- Department of Respiratory and Critical Care Medicine, Frontiers Science Center for Disease-related Molecular Network, Center of Precision Medicine, Precision Medicine Key Laboratory of Sichuan Province, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.
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Li Y, Wu Z, Ni C, Li Y, Wang P. Evaluation of the clinical significance of lymphocyte subsets and myeloid suppressor cells in patients with renal carcinoma. Discov Oncol 2024; 15:512. [PMID: 39347882 PMCID: PMC11442913 DOI: 10.1007/s12672-024-01405-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/17/2024] [Accepted: 09/27/2024] [Indexed: 10/01/2024] Open
Abstract
PURPOSE The purpose of this study was to analyze the expression patterns of immune cells in renal cancer patients, including myeloid-derived suppressor cells (MDSCs), regulatory T cells (Tregs), CD3 + /CD4 + T cells, CD3 + / CD8 + T cells, and CD3- CD16 + CD56 + cells. In addition, this study will explore the correlation between these immune markers and the progression of renal cell carcinoma and evaluate their potential application in predicting the therapeutic effect of renal cell carcinoma. METHODS In this study, 80 renal cancer patients who received treatment in our hospital from October 2022 to December 2023 were selected as the research object and 50 healthy people who underwent a physical examination at the same time were selected as the control group. All participants had a 3 ml venous blood sample taken in the morning on an empty stomach. All patients with renal cell carcinoma have been confirmed by histopathological diagnosis. Clinicopathological data including age, gender, BMI, clinical stage, tumor size and pathological type were collected.MDSC, Treg, CD3 + /CD4 + T cells, CD3 + /CD8 + T cells, the ratio of CD3 + /CD4 + T cells/CD3 + /CD8 + T cell and the expression level of CD3-CD16 + CD56 + cells were detected by flow cytometry. RESULTS Through the detection of flow cytometry, we observed that there was no significant difference in gender, age, BMI and other baseline characteristics between renal cancer patients and healthy controls, and the P value was greater than 0.05. However, in the analysis of peripheral blood immune cell subsets, including CD3 + /CD4 + , CD3 + /CD8 + , CD3 + /CD4 + /CD3 + /CD8 + ratio, NK cells, regulatory T cells (T-reg), polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC) and mononuclear myeloid-derived suppressor cells (M-MDSC) were significantly different between renal cell carcinoma group and normal control group (P < 0.05). Specifically, the expression levels of CD3 + /CD4 + and CD3 + /CD8 + cells in renal cancer patients were lower than those in normal subjects, while the expression levels of T-reg, PMN-MDSC and M-MDSC were relatively high. (2) In the flow cytometry analysis, the expression level of immune cell subsets in the peripheral blood of renal cancer patients was detected.The results showed that there was no significant correlation between the expression of CD3 + /CD4 + , CD3 + /CD8 + , CD3 + /CD4 + /CD3 + /CD8 + ratio, NK cells, T-reg cells, PMN-MDSC and M-MDSC and the sex, age, BMI and pathological type of the patients. These differences were not statistically significant (P > 0.05).At the same time, CD3 + /CD8 + T cells, the ratio of CD3 + /CD4 + /CD3 + /CD8 + and the expression level of NK cells were not significantly correlated with tumor size and clinical stage (P > 0.05). However, the expression levels of CD3 + /CD4 + cells, M-MDSC, PMN-MDSC, and T-reg cells were statistically significantly different with tumor size and clinical stage (P < 0.05).There was a significant difference between these indexes and lymph node metastasis (P < 0.05). (3) The results of Logistic regression analysis showed that the low expression of CD3 + /CD4 + lymphocytes and the high expression of T-reg, PMN-MDSC and M-MDSC in peripheral blood may be related to the clinical stage of renal cell carcinoma. CONCLUSION (1) Compared with healthy individuals, patients with renal cell carcinoma showed a significant decrease in CD3 + /CD4 + T cells, CD3 + /CD8 + T cells and CD3-CD16 + CD56 + cells, while the CD4 + /CD8 + ratio increased. In addition, the number of PMN-MDSC, M-MDSC and T-reg cells was significantly increased compared with the normal population, indicating that the immune system function of patients was impaired. (2) The expression levels of CD3 + /CD4 + , PMN-MDSC, M-MDSC and T-reg were different in tumor size and clinical stage. Specifically, the expression levels of PMN-MDSC, M-MDSC, and T-reg increased correspondingly with the increase in tumor diameter and the progression of the clinical stage.
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Affiliation(s)
- Yan Li
- Department of Nephrology, Third People's Hospital of Hangzhou, Hangzhou, 310009, Zhejiang, China.
| | - Zhiping Wu
- Department of Nephrology, Third People's Hospital of Hangzhou, Hangzhou, 310009, Zhejiang, China
| | - Chen Ni
- Department of Nephrology, Third People's Hospital of Hangzhou, Hangzhou, 310009, Zhejiang, China
| | - Yueda Li
- Department of Nephrology, Third People's Hospital of Hangzhou, Hangzhou, 310009, Zhejiang, China
| | - Ping Wang
- Department of Nephrology, Third People's Hospital of Hangzhou, Hangzhou, 310009, Zhejiang, China
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Wu M, Wu S, Guo R. Upregulation of ZMAT3 is Associated with the Poor Prognosis of Breast Cancer. Int J Gen Med 2024; 17:4003-4014. [PMID: 39286533 PMCID: PMC11404498 DOI: 10.2147/ijgm.s470303] [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: 05/20/2024] [Accepted: 09/08/2024] [Indexed: 09/19/2024] Open
Abstract
Background Breast cancer is the leading cause of cancer-related deaths among women worldwide. Identifying robust biomarkers for predicting outcomes is essential for improving patient care and reducing fatalities. ZMAT3, a zinc finger protein with potential carcinogenic properties, has been associated with various cancers. However, its role in breast cancer prognosis remains unclear. Methods We investigated the expression level of ZMAT3 in breast cancer tissues and its association with clinical outcomes through bioinformatics analysis and experimental validation. We examined the correlation between ZMAT3 expression and immune characteristics. ZMAT3 mRNA expression data from The Cancer Genome Atlas (TCGA) were analysed in relation to overall survival (OS), disease-specific survival (DSS) and progression-free interval (PFI) in patients with breast cancer. Immunohistochemistry (IHC) was performed on breast cancer tissues to assess ZMAT3 protein levels, with findings validated using qPCR and cell experiments. Results ZMAT3 mRNA levels were significantly upregulated in breast cancer samples compared to normal tissues. High ZMAT3 expression was significantly correlated with the poor OS, DSS and PFI. A significant positive correlation was observed between high ZMAT3 mRNA levels and the abundance of tumour-infiltrating lymphocytes (TILs), especially CD8+T cells and regulatory T cells (Tregs). Multivariate Cox regression analysis identified ZMAT3 as an independent prognostic factor for breast cancer. IHC staining confirmed increased ZMAT3 protein expression in breast cancer tissues, which was further validated by qPCR and cell function tests. Conclusion Our findings suggest that ZMAT3 is a prognostic biomarker linked to immune invasion in breast cancer. Elevated ZMAT3 expression correlates with adverse clinical outcomes, indicating its potential role in disease progression.
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Affiliation(s)
- Meng Wu
- Department of Pharmacy, the First Hospital of China Medical University, Shenyang, 110001, People's Republic of China
| | - Shuang Wu
- Department of Pharmacy, the First Hospital of China Medical University, Shenyang, 110001, People's Republic of China
| | - Rui Guo
- Department of Critical Care Medicine, the First Hospital of China Medical University, Shenyang, 110001, People's Republic of China
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Xu J, Tian Y, Zhao B, Hu D, Wu S, Ma J, Yang L. Gut microbiome influences efficacy of Endostatin combined with PD-1 blockade against colorectal cancer. MOLECULAR BIOMEDICINE 2024; 5:37. [PMID: 39251538 PMCID: PMC11383918 DOI: 10.1186/s43556-024-00200-3] [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: 05/10/2024] [Accepted: 08/13/2024] [Indexed: 09/11/2024] Open
Abstract
The combination of anti-angiogenic drugs and immune checkpoint inhibitors (ICIs) in the treatment of tumors is emerging as a way to improve ICIs-resistant tumor therapy. In addition, gut microbes (GMs) are involved in angiogenesis in the tumor microenvironment and are also associated with the antitumor function of immune checkpoint inhibitors. However, it is unclear whether gut microbes have a role in anti-tumor function in the combination of anti-angiogenic drugs and immune checkpoint inhibitors for cancer treatment. Endostatin, an angiogenesis inhibitor, has been widely used as an antiangiogenic therapy for cancer. We showed that combined therapy with an adenovirus encoding human endostatin, named Ad-E, and PD-1 blockade dramatically abrogated MC38 tumor growth. The structure of intestinal microbes in mice was changed after combination treatment. We found that the antitumor function of combination therapy was inhibited after the elimination of intestinal microbes. In mice with depleted microbiota, oral gavage of Bacteroides fragilis salvaged the antitumor effects of combination Ad-E and αPD-1 monoclonal antibody (mAb) to a certain extent. Further, Bacteroides fragilis could improve CD3+T cells, NK cells, and IFNγ+CD8+ T cells in the tumor microenvironment to inhibit tumor growth. Besides, Bacteroides fragilis might restore antitumor function by down-regulating isobutyric acid (IBA). Our results suggested that GMs may be involved in the combination of Ad-E and αPD-1 mAb for cancer treatment, which has oncological implications for tumor growth dynamics and cancer immune surveillance.
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Affiliation(s)
- Jie Xu
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, No. 17, West China Hospital, Sichuan University, Section 3, South Renmin Road, Chengdu, 610041, Sichuan, The People's Republic of China
| | - Yaomei Tian
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, No. 17, West China Hospital, Sichuan University, Section 3, South Renmin Road, Chengdu, 610041, Sichuan, The People's Republic of China
- College of Bioengineering, Sichuan University of Science & Engineering, No. 519, Huixing Road, Zigong, Sichuan, 643000, The People's Republic of China
| | - Binyan Zhao
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, No. 17, West China Hospital, Sichuan University, Section 3, South Renmin Road, Chengdu, 610041, Sichuan, The People's Republic of China
| | - Die Hu
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, No. 17, West China Hospital, Sichuan University, Section 3, South Renmin Road, Chengdu, 610041, Sichuan, The People's Republic of China
| | - Siwen Wu
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, No. 17, West China Hospital, Sichuan University, Section 3, South Renmin Road, Chengdu, 610041, Sichuan, The People's Republic of China
| | - Jing Ma
- Biological Products Inspection Institute of Sichuan Institute of Drug Inspection, Sichuan, The People's Republic of China.
| | - Li Yang
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, No. 17, West China Hospital, Sichuan University, Section 3, South Renmin Road, Chengdu, 610041, Sichuan, The People's Republic of China.
- Frontiers Medical Center, Tianfu Jincheng Laboratory, Chengdu, 610212, China.
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Santos TPMD, Hicks WL, Magner WJ, Al Afif A, Kirkwood KL. Metabolic and Aging Influence on Anticancer Immunity in Oral Cancer. J Dent Res 2024; 103:953-961. [PMID: 39185914 DOI: 10.1177/00220345241264728] [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: 08/27/2024] Open
Abstract
The average age and obesity prevalence are increasing globally. Both aging and metabolic disease burden increase the risk of oral squamous cell carcinoma (OSCC) through profound effects on the immunological and metabolic characteristics within the OSCC tumor microenvironment. While the mechanisms that link aging and obesity to OSCC remain unclear, there is evidence that the antitumor responses are diminished in both conditions. Remarkably, however, immune checkpoint blockade, a form of cancer immunotherapy, remains intact despite the enhanced immunosuppressive tumor microenvironment in the context of either aging or obesity. Herein, we review the current knowledge of how aging and systemic metabolic changes affect antitumor immunity with an emphasis on the role of tumor-associated macrophages that greatly contribute to tumor immunosuppression. Key aspects discussed include the mechanisms of angiogenesis, cytokine release, phagocytosis attenuation, and immune cell recruitment during obesity and aging that create an immune-suppressive tumor microenvironment by recruitment and repolarization of tumor-associated macrophages. Through a deeper appreciation of these mechanisms, the development of novel therapeutic approaches to control OSCC will provide more refined management of the tumor microenvironment in the context of aging and obesity.
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Affiliation(s)
- T P M D Santos
- Department of Oral Biology, School of Dental Medicine, University at Buffalo, Buffalo, NY, USA
- Department of Head & Neck/Plastic and Reconstructive Surgery, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - W L Hicks
- Department of Head & Neck/Plastic and Reconstructive Surgery, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - W J Magner
- Department of Head & Neck/Plastic and Reconstructive Surgery, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - A Al Afif
- Department of Head & Neck/Plastic and Reconstructive Surgery, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - K L Kirkwood
- Department of Oral Biology, School of Dental Medicine, University at Buffalo, Buffalo, NY, USA
- Department of Head & Neck/Plastic and Reconstructive Surgery, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
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Ezaki A, Yano H, Pan C, Fujiwara Y, Anami T, Ibe Y, Motoshima T, Yatsuda J, Esumi S, Miura Y, Kamba T, Komohara Y. Potential protumor function of CD74 in clear cell renal cell carcinoma. Hum Cell 2024; 37:1535-1543. [PMID: 39080216 DOI: 10.1007/s13577-024-01110-w] [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: 03/12/2024] [Accepted: 07/22/2024] [Indexed: 08/23/2024]
Abstract
CD74 is a transmembrane protein that functions as a specialized chaperone of HLA class II and CD74 in tumor cells was suggested to be involved in cell proliferation in several kinds of malignant tumors. CD74 is also known to be expressed in macrophages, therefore, we investigated the CD74 expression in clear cell renal cell carcinoma (ccRCC). Immunohistochemistry of CD74 indicated that CD74 was expressed not only in cancer cells but also macrophages. CD74 was detected in surface membrane and cytoplasm of cancer cells in 92 of 94 cases (98%) and of 87 of 94 cases (93%). CD74 was expressed both in cancer cells and TAMs in 86 of 94 cases (91%). In vitro studies using cancer cell lines and monocyte-derived macrophages stimulated by anti-CD74 antibodies showed that CD74 signal accelerated cancer cell proliferation and macrophage activation. However, macrophage activation via CD74 signal did not influence macrophage-mediated cancer cell growth. RNA-sequence of macrophages stimulated by anti-CD74 antibodies indicated that CD74 signal was associated to inflammatory responses in macrophages. In conclusion, we examined the expression and functional significance of CD74 in ccRCC using tissue specimens and cell culture studies. The function of CD74 was suggested to be different in cancer cells and in macrophages, and further studies are necessary to clarify the functional significance of CD74 in ccRCC.
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MESH Headings
- Carcinoma, Renal Cell/pathology
- Carcinoma, Renal Cell/genetics
- Carcinoma, Renal Cell/metabolism
- Humans
- Kidney Neoplasms/pathology
- Kidney Neoplasms/genetics
- Kidney Neoplasms/metabolism
- Antigens, Differentiation, B-Lymphocyte/metabolism
- Antigens, Differentiation, B-Lymphocyte/genetics
- Antigens, Differentiation, B-Lymphocyte/physiology
- Cell Proliferation/genetics
- Histocompatibility Antigens Class II/metabolism
- Macrophages/metabolism
- Macrophages/immunology
- Cell Line, Tumor
- Macrophage Activation/genetics
- Gene Expression/genetics
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Affiliation(s)
- Ayano Ezaki
- Department of Cell Pathology, Graduate School of Medical Sciences, Kumamoto University, 1-1-1, Honjo, Kumamoto Chuo-Ku, Kumamoto, 860-8556, Japan
| | - Hiromu Yano
- Department of Cell Pathology, Graduate School of Medical Sciences, Kumamoto University, 1-1-1, Honjo, Kumamoto Chuo-Ku, Kumamoto, 860-8556, Japan
| | - Cheng Pan
- Department of Cell Pathology, Graduate School of Medical Sciences, Kumamoto University, 1-1-1, Honjo, Kumamoto Chuo-Ku, Kumamoto, 860-8556, Japan
| | - Yukio Fujiwara
- Department of Cell Pathology, Graduate School of Medical Sciences, Kumamoto University, 1-1-1, Honjo, Kumamoto Chuo-Ku, Kumamoto, 860-8556, Japan
| | - Toshiki Anami
- Department of Cell Pathology, Graduate School of Medical Sciences, Kumamoto University, 1-1-1, Honjo, Kumamoto Chuo-Ku, Kumamoto, 860-8556, Japan
- Department of Urology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Yuki Ibe
- Department of Cell Pathology, Graduate School of Medical Sciences, Kumamoto University, 1-1-1, Honjo, Kumamoto Chuo-Ku, Kumamoto, 860-8556, Japan
- Department of Urology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Takanobu Motoshima
- Department of Urology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Junji Yatsuda
- Department of Urology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Shigeyuki Esumi
- Department of Anatomy and Neurobiology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Yuji Miura
- Department of Cell Pathology, Graduate School of Medical Sciences, Kumamoto University, 1-1-1, Honjo, Kumamoto Chuo-Ku, Kumamoto, 860-8556, Japan
- Department of Medical Oncology, Toranomon Hospital, Tokyo, Japan
| | - Tomomi Kamba
- Department of Urology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Yoshihiro Komohara
- Department of Cell Pathology, Graduate School of Medical Sciences, Kumamoto University, 1-1-1, Honjo, Kumamoto Chuo-Ku, Kumamoto, 860-8556, Japan.
- Center for Metabolic Regulation of Healthy Aging, Kumamoto University, Kumamoto, Japan.
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Yang Z, Deng X, Wen D, Sun L, An R, Xu J. Identification of RCAN1's role in hepatocellular carcinoma using single-cell analysis. BMC Cancer 2024; 24:1056. [PMID: 39192218 PMCID: PMC11348566 DOI: 10.1186/s12885-024-12807-4] [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: 01/31/2024] [Accepted: 08/14/2024] [Indexed: 08/29/2024] Open
Abstract
BACKGROUND The regulator of calcineurin 1 (RCAN1) is expressed in multiple organs, including the heart, liver, brain, and kidney, and is closely linked to the pathogenesis of cardiovascular diseases, Down syndrome, and Alzheimer's disease. It is also implicated in the development of various organ tumors; however, its potential role in hepatocellular carcinoma (HCC) remains poorly understood. Therefore, the objective of this study was to investigate the potential mechanisms of RCAN1 in HCC through bioinformatics analysis. METHODS We conducted a joint analysis based on the NCBI and TCGA databases, integrating both bulk transcriptome and single-cell analyses to examine the principal biological functions of RCAN1 in HCC, as well as its roles related to phenotype, metabolism, and cell communication. Subsequently, an RCAN1-overexpressing cell line was established, and the effects of RCAN1 on tumor cells were validated through in vitro experiments. Moreover, we endeavored to identify potential related drugs using molecular docking and molecular dynamics simulations. RESULTS The expression of RCAN1 was found to be downregulated in 19 types of cancer tissues and upregulated in 11 types of cancer tissues. Higher levels of RCAN1 expression were associated with improved patient survival. RCAN1 was predominantly expressed in hepatocytes, macrophages, endothelial cells, and monocytes, and its high expression not only closely correlated with the distribution of cells related to the HCC phenotype but also with the distribution of HCC cells themselves. Additionally, Rcan1 may directly or indirectly participate in metabolic pathways such as alanine, aspartate, and glutamate metabolism, as well as butanoate metabolism, thereby influencing tumor cell proliferation and migration. In vitro experiments confirmed that RCAN1 overexpression promoted apoptosis while inhibiting proliferation and invasion of HCC cells. Through molecular docking of 1615 drugs, we screened brompheniramine as a potential target drug and verified our results by molecular dynamics. CONCLUSION In this study, we revealed the relationship between RCAN1 and HCC through bioinformatics methods, verified that RCAN1 can affect the progress of the disease through experiments, and finally identified potential therapeutic drugs through drug molecular docking and molecular dynamics.
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Affiliation(s)
- Ziqi Yang
- Department of Radiology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
- Department of Interventional Surgery Center, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Xiwei Deng
- Department of Radiology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
- Department of Interventional Surgery Center, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
- Department of Oncology, Bethune International Peace Hospital, Shijiazhuang, Hebei, China
| | - Didi Wen
- Department of Radiology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Lijun Sun
- Department of Radiology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
- Department of Interventional Surgery Center, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Rui An
- Department of Radiology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China.
- Department of Interventional Surgery Center, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China.
| | - Jian Xu
- Department of Radiology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China.
- Department of Interventional Surgery Center, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China.
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Ferreira-Silva GÁ, Rodrigues DA, Pressete CG, Caixeta ES, Gamero AMC, Miyazawa M, Hanemann JAC, Fraga CAM, Aissa AF, Ionta M. Selective inhibition of HDAC6 by N-acylhydrazone derivative reduces the proliferation and induces senescence in carcinoma hepatocellular cells. Toxicol In Vitro 2024; 99:105884. [PMID: 38945376 DOI: 10.1016/j.tiv.2024.105884] [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: 05/03/2024] [Revised: 06/13/2024] [Accepted: 06/25/2024] [Indexed: 07/02/2024]
Abstract
Hepatocellular carcinoma (HCC) is a significant contributor to cancer-related deaths globally. Systemic therapy is the only treatment option for HCC at an advanced stage, with limited therapeutic response. In this study, we evaluated the antitumor potential of four N-acylhydrazone (NAH) derivatives, namely LASSBio-1909, 1911, 1935, and 1936, on HCC cell lines. We have previously demonstrated that the aforementioned NAH derivatives selectively inhibit histone deacetylase 6 (HDAC6) in lung cancer cells, but their effects on HCC cells have not been explored. Thus, the present study aimed to evaluate the effects of NAH derivatives on the proliferative behavior of HCC cells. LASSBio-1911 was the most cytotoxic compound against HCC cells, however its effects were minimal on normal cells. Our results showed that LASSBio-1911 inhibited HDAC6 in HCC cells leading to cell cycle arrest and decreased cell proliferation. There was also an increase in the frequency of cells in mitosis onset, which was associated with disturbing mitotic spindle formation. These events were accompanied by elevated levels of CDKN1A mRNA, accumulation of CCNB1 protein, and sustained ERK1 phosphorylation. Furthermore, LASSBio-1911 induced DNA damage, resulting in senescence and/or apoptosis. Our findings indicate that selective inhibition of HDAC6 may provide an effective therapeutic strategy for the treatment of advanced HCC, including tumor subtypes with integrated viral genome. Further, in vivo studies are required to validate the antitumor effect of LASSBio-1911 on liver cancer.
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Affiliation(s)
| | - Daniel Alencar Rodrigues
- Laboratory of Evaluation and Synthesis of Bioactive Substances (LASSBio), Institute of Biomedical Sciences, Federal University of Rio de Janeiro, CCS, Rio de Janeiro, RJ, Brazil
| | | | | | - Angel Mauricio Castro Gamero
- Human Genetics Laboratory, Institute of Natural Science, Federal University of Alfenas, zip-code 37130-001, Alfenas, MG, Brazil
| | - Marta Miyazawa
- School of Dentistry, Federal University of Alfenas, 37130-001 MG, Brazil
| | | | - Carlos Alberto Manssour Fraga
- Laboratory of Evaluation and Synthesis of Bioactive Substances (LASSBio), Institute of Biomedical Sciences, Federal University of Rio de Janeiro, CCS, Rio de Janeiro, RJ, Brazil
| | - Alexandre Ferro Aissa
- Institute of Biomedical Sciences, Federal University of Alfenas, MG 37130-001, Brazil.
| | - Marisa Ionta
- Institute of Biomedical Sciences, Federal University of Alfenas, MG 37130-001, Brazil.
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Ni JR, Zhang QH, Deng JL, Wang HH, Duan YC, Zhang CJ, Jiang LT. Promotion Effect of Catalpol on Angiogenesis and Potential Mechanisms: A Research Based on Network Pharmacology. Chem Biol Drug Des 2024; 104:e14602. [PMID: 39134897 DOI: 10.1111/cbdd.14602] [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: 10/20/2023] [Revised: 06/11/2024] [Accepted: 07/23/2024] [Indexed: 08/18/2024]
Abstract
Catalpol, a natural iridoid glycoside, has potential therapeutic benefits, including anti-inflammatory and neuroprotective effects. Investigating catalpol's role in angiogenesis is critical for understanding its potential therapeutic applications, particularly in diseases where modulating angiogenesis is beneficial. This study investigates catalpol's influence on angiogenesis and its mechanisms, combining network pharmacology and in vitro experiments. The target genes corresponding to the catalpol were analyzed by SwissTargetPrediction. Then angiogenesis-related targets were acquired from databases like GeneCards. Subsequently, the Database for Annotation, Visualization and Integrated Discovery was employed for Gene Ontology and pathway analysis, while Cytoscape visualized protein interactions. The effect of catalpol on viability and angiogenesis of HUVECs was further examined using Cell Counting Kit-8 and angiogenesis assays. RT-qPCR and western blot were applied to check the expression of angiogenesis-related proteins. Totally, 312 target genes of catalpol and 823 angiogenesis-related targets were obtained with 56 common targets leading to PPI network analysis, highlighting hub genes (AKT1, EGFR, STAT3, MAPK3, and CASP3). These hub genes were mainly enriched in lipid and atherosclerosis pathway and EGFR-related pathway. The in vitro experimental results showed that catalpol achieved a concentration-dependent increase in HUVECs viability. Catalpol also promoted the migration and angiogenesis of HUVECs and up-regulated the expression of EGFR. EGFR knockdown inhibited the effect of catalpol on HUVECs. Catalpol promotes angiogenesis in HUVECs by upregulating EGFR and angiogenesis-related proteins, indicating its potential therapeutic application in vascular-related diseases.
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Affiliation(s)
- Jin-Rong Ni
- Department of Orthopedics, Jiangsu Province (Suqian) Hospital, Suqian, China
| | - Qun-Hu Zhang
- Department of Orthopedics, Jiangsu Province (Suqian) Hospital, Suqian, China
| | - Jie-Lin Deng
- Department of Orthopedics, Jiangsu Province (Suqian) Hospital, Suqian, China
| | - Hai-Hu Wang
- Department of Orthopedics, Jiangsu Province (Suqian) Hospital, Suqian, China
| | - Yong-Chi Duan
- Department of Orthopedics, Jiangsu Province (Suqian) Hospital, Suqian, China
| | - Cheng-Ji Zhang
- Department of Orthopedics, Jiangsu Province (Suqian) Hospital, Suqian, China
| | - Lue-Tao Jiang
- Department of Orthopedics, Jiangsu Province (Suqian) Hospital, Suqian, China
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Msaouel P, Sweis RF, Bupathi M, Heath E, Goodman OB, Hoimes CJ, Milowsky MI, Davis N, Kalebasty AR, Picus J, Shaffer D, Mao S, Adra N, Yorio J, Gandhi S, Grivas P, Siefker-Radtke A, Yang R, Latven L, Olson P, Chin CD, Der-Torossian H, Mortazavi A, Iyer G. A Phase 2 Study of Sitravatinib in Combination with Nivolumab in Patients with Advanced or Metastatic Urothelial Carcinoma. Eur Urol Oncol 2024; 7:933-943. [PMID: 38105142 DOI: 10.1016/j.euo.2023.12.001] [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: 10/18/2023] [Revised: 11/16/2023] [Accepted: 12/01/2023] [Indexed: 12/19/2023]
Abstract
BACKGROUND AND OBJECTIVE Checkpoint inhibitor therapy (CPI) has demonstrated survival benefits in urothelial carcinoma (UC); however, not all patients benefit from CPI due to resistance. Combining sitravatinib, a multitargeted receptor tyrosine kinase inhibitor of TYRO3, AXL, and MERTK (TAM) receptors and VEGFR2, with CPI may improve antitumor responses. Our objective was to assess the efficacy and safety of sitravatinib plus nivolumab in patients with advanced/metastatic UC. METHODS The 516-003 trial (NCT03606174) is an open-label, multicohort phase 2 study evaluating sitravatinib plus nivolumab in patients with advanced/metastatic UC enrolled in eight cohorts depending on prior treatment with CPI, platinum-based chemotherapy (PBC), or antibody-drug conjugate (ADC). Overall, 244 patients were enrolled and treated with sitravatinib plus nivolumab (median follow-up 14.1-38.2 mo). Sitravatinib (free-base capsules 120 mg once daily [QD] or malate capsule 100 mg QD) plus nivolumab (240 mg every 2 wk/480 mg every 4 wk intravenously). KEY FINDINGS AND LIMITATIONS The primary endpoint was objective response rate (ORR; RECIST v1.1). The secondary endpoints included progression-free survival (PFS) and safety. The Predictive probability design and confidence interval methods were used. Among patients previously treated with PBC, ORR, and median PFS were 32.1% and 3.9 mo in CPI-naïve patients (n = 53), 14.9% and 3.9 mo in CPI-refractory patients (n = 67), and 5.4% and 3.7 mo in CPI- and ADC-refractory patients (n = 56), respectively. Across all cohorts, grade 3 treatment-related adverse events (TRAEs) occurred in 51.2% patients and grade 4 in 3.3%, with one treatment-related death (cardiac failure). Immune-related adverse events occurred in 50.4% patients. TRAEs led to sitravatinib/nivolumab discontinuation in 6.1% patients. CONCLUSIONS AND CLINICAL IMPLICATIONS Sitravatinib plus nivolumab demonstrated a manageable safety profile but did not result in clinically meaningful ORRs in patients with advanced/metastatic UC in the eight cohorts studied. PATIENT SUMMARY In this study, the combination of two anticancer drugs, sitravatinib and nivolumab, resulted in manageable side effects but no meaningful responses in patients with bladder cancer.
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Affiliation(s)
- Pavlos Msaouel
- University of Texas MD Anderson Cancer Center, Houston, TX, USA.
| | | | | | | | - Oscar B Goodman
- Comprehensive Cancer Centers of Nevada - Southwest, Las Vegas, NV, USA
| | | | | | - Nancy Davis
- Vanderbilt - Ingram Cancer Center, Nashville, TN, USA
| | | | - Joel Picus
- Washington University School of Medicine, Siteman Cancer Center, Saint Louis, MO, USA
| | - David Shaffer
- New York Oncology Hematology - Albany Medical Center, Albany, NY, USA
| | - Shifeng Mao
- Allegheny General Hospital, Pittsburgh, PA, USA
| | - Nabil Adra
- Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN, USA
| | | | - Sunil Gandhi
- Florida Cancer Specialists and Research Institute - North Region (SCRI), Tampa Bay, FL, USA
| | - Petros Grivas
- Fred Hutchinson Cancer Center, University of Washington, Seattle, WA, USA
| | | | - Rui Yang
- Mirati Therapeutics, Inc., San Diego, CA, USA
| | - Lisa Latven
- Mirati Therapeutics, Inc., San Diego, CA, USA
| | - Peter Olson
- Mirati Therapeutics, Inc., San Diego, CA, USA
| | | | | | - Amir Mortazavi
- Division of Medical Oncology, Department of Internal Medicine, College of Medicine, The Ohio State University, and the Comprehensive Cancer Center, Columbus, OH, USA
| | - Gopa Iyer
- Memorial Sloan Kettering Cancer Center, New York, NY, USA
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50
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Wang F, Zhang S, Sun F, Chen W, Liu C, Dong H, Cui B, Li L, Sun C, Du W, Liu B, Fan W, Deng J, Schmitt CA, Wang X, Du J. Anti-angiogenesis and anti-immunosuppression gene therapy through targeting COUP-TFII in an in situ glioblastoma mouse model. Cancer Gene Ther 2024; 31:1135-1150. [PMID: 38926596 DOI: 10.1038/s41417-024-00799-z] [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: 02/27/2024] [Revised: 06/05/2024] [Accepted: 06/13/2024] [Indexed: 06/28/2024]
Abstract
Glioblastoma (GBM) is the most common and aggressive primary brain cancer; angiogenesis and immunosuppression exacerbate GBM progression. COUP-TFII demonstrates pro-angiogenesis activity; however, its role in glioma progression remains unclear. This study revealed that COUP-TFII promotes angiogenesis in gliomas by inducing transdifferentiation of glioma cells into endothelial-like cells. Mechanistic investigation suggested that COUP-TFII as a transcription factor exerts its function via binding to the promoter of TXNIP. Interestingly, COUP-TFII knockdown attenuated tumorigenesis and tumor progression in an immunocompetent mouse model but promoted tumor progression in an immuno-deficient mouse model. As an explanation, repression of COUP-TFII induces cellular senescence and activates immune surveillance in glioma cells in vitro and in vivo. In addition, we used heparin-polyethyleneimine (HPEI) nanoparticles to deliver COUP-TFII shRNA, which regulated tumor angiogenesis and immunosuppression in an in situ GBM mouse model. This study provides a novel strategy and potential therapeutic targets to treat GBM.
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Affiliation(s)
- Fei Wang
- Medical Research Center, Binzhou Medical University Hospital, 256600, Binzhou, PR China
- Medical Integration and Practice Center, Qilu Hospital of Shandong University, Shandong University, 250100, Jinan, PR China
| | - Shuo Zhang
- Medical Research Center, Binzhou Medical University Hospital, 256600, Binzhou, PR China
- Department of Gynecology, Binzhou Medical University Hospital, 256600, Binzhou, PR China
| | - Fengjiao Sun
- Medical Research Center, Binzhou Medical University Hospital, 256600, Binzhou, PR China
| | - Weiwei Chen
- Medical Research Center, Binzhou Medical University Hospital, 256600, Binzhou, PR China
| | - Cuilan Liu
- Medical Research Center, Binzhou Medical University Hospital, 256600, Binzhou, PR China
| | - Hongliang Dong
- Medical Research Center, Binzhou Medical University Hospital, 256600, Binzhou, PR China
| | - Bingjie Cui
- Medical Research Center, Binzhou Medical University Hospital, 256600, Binzhou, PR China
| | - Lingyu Li
- Medical Research Center, Binzhou Medical University Hospital, 256600, Binzhou, PR China
| | - Chunlong Sun
- College of Biological and Environmental Engineering, Shandong University of Aeronautics, 256600, Binzhou, PR China
| | - Wen Du
- College of Biological and Environmental Engineering, Shandong University of Aeronautics, 256600, Binzhou, PR China
| | - Bin Liu
- Medical Research Center, Binzhou Medical University Hospital, 256600, Binzhou, PR China
| | - Wanfeng Fan
- Medical Research Center, Binzhou Medical University Hospital, 256600, Binzhou, PR China
| | - Jiong Deng
- Medical Research Center, Binzhou Medical University Hospital, 256600, Binzhou, PR China
| | - Clemens A Schmitt
- Johannes Kepler University, Altenbergerstraße 69, 4040, Linz, Austria
- Department of Hematology and Oncology, Kepler University Hospital, Krankenhausstraße 9, 4020, Linz, Austria
- Medical Department of Hematology, Oncology and Tumor Immunology, and Molekulares Krebsforschungszentrum - MKFZ, Campus Virchow Klinikum, Charité-Universitätsmedizin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 13353, Berlin, Germany
- Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Robert-Rössle-Straße 10, 13125, Berlin, Germany
- Deutsches Konsortium für Translationale Krebsforschung (German Cancer Consortium), Partner Site, Berlin, Germany
| | - Xiuwen Wang
- Medical Integration and Practice Center, Qilu Hospital of Shandong University, Shandong University, 250100, Jinan, PR China.
| | - Jing Du
- Medical Research Center, Binzhou Medical University Hospital, 256600, Binzhou, PR China.
- Department of Gynecology, Binzhou Medical University Hospital, 256600, Binzhou, PR China.
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