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Sultan MH, Zhan Q, Wang Y, Xia Y, Jia X. Precision oncolytic viral therapy in colorectal cancer: Genetic targeting and immune modulation for personalized treatment (Review). Int J Mol Med 2025; 56:104. [PMID: 40342021 PMCID: PMC12081034 DOI: 10.3892/ijmm.2025.5545] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2024] [Accepted: 04/09/2025] [Indexed: 05/11/2025] Open
Abstract
Colorectal cancer (CRC) is a leading health issue and treatments to eradicate it, such as conventional chemotherapy, are non‑selective and come with a number of complications. The present review focuses on the relatively new area of precision oncolytic viral therapy (OVT), with genetic targeting and immune modifications that offer a new future for CRC treatment. In the present review, an overview of the selection factors that are considered optimal for an oncolytic virus, mechanisms of oncolysis and immunomodulation applied to the OVT, as well as new strategies to improve the efficacy of this method are described. Additionally, cause‑and‑effect relationships are examined for OVT efficacy, mediated by the tumor microenvironment, and directions for genetic manipulation of viral specificity are explored. The possibility of synergy between OVT and immune checkpoint inhibitors and other treatment approaches are demonstrated. Incorporating the details of the present review, biomarker‑guided combination therapies in precision OVT for individualized CRC care, significant issues and future trends in this required area of medicine are highlighted. Increasingly, OVT is leaving the experimental stage and may become routine practice; it provides a new perspective on overcoming CRC and highlights the importance of further research and clinical work.
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Affiliation(s)
- Muhammad Haris Sultan
- College of Life Sciences and Medicine, Xinyuan Institute of Medicine and Biotechnology, Zhejiang Sci-Tech University, Hangzhou, Zhejiang 310018, P.R. China
- Center for Translational Medicine and Precision Medicine, Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, Zhejiang 325000, P.R. China
| | - Qi Zhan
- College of Life Sciences and Medicine, Xinyuan Institute of Medicine and Biotechnology, Zhejiang Sci-Tech University, Hangzhou, Zhejiang 310018, P.R. China
| | - Yigang Wang
- College of Life Sciences and Medicine, Xinyuan Institute of Medicine and Biotechnology, Zhejiang Sci-Tech University, Hangzhou, Zhejiang 310018, P.R. China
| | - Yulong Xia
- Center for Translational Medicine and Precision Medicine, Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, Zhejiang 325000, P.R. China
| | - Xiaoyuan Jia
- College of Life Sciences and Medicine, Xinyuan Institute of Medicine and Biotechnology, Zhejiang Sci-Tech University, Hangzhou, Zhejiang 310018, P.R. China
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Lou E, Choudhry MS, Starr TK, Folsom TD, Bell J, Rathmann B, DeFeo AP, Kim J, Slipek N, Jin Z, Sumstad D, Klebanoff CA, Ladner K, Sarkari A, McIvor RS, Murray TA, Miller JS, Rao M, Jensen E, Ankeny J, Khalifa MA, Chauhan A, Spilseth B, Dixit A, Provenzano PP, Pan W, Weber D, Byrne-Steele M, Henley T, McKenna DH, Johnson MJ, Webber BR, Moriarity BS. Targeting the intracellular immune checkpoint CISH with CRISPR-Cas9-edited T cells in patients with metastatic colorectal cancer: a first-in-human, single-centre, phase 1 trial. Lancet Oncol 2025; 26:559-570. [PMID: 40315882 DOI: 10.1016/s1470-2045(25)00083-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2025] [Revised: 02/07/2025] [Accepted: 02/11/2025] [Indexed: 05/04/2025]
Abstract
BACKGROUND Over the past decade, immunotherapeutic strategies-mainly targeting the PD-1-PD-L1 immune checkpoint axis-have altered cancer treatment for many solid tumours, but few patients with gastrointestinal forms of cancer have benefited to date. There remains an urgent need to extend immunotherapy efficacy to more patients while addressing resistance to current immune checkpoint inhibitors. The aim of this study was to determine the safety and anti-tumour activity of knockout of CISH, which encodes cytokine-inducible SH2-containing protein, a novel intracellular immune checkpoint target and a founding member of the SOCS family of E3-ligases, using tumour infiltrating lymphocyte (TILs) genetically edited with CRISPR-Cas9 in patients with metastatic gastrointestinal epithelial cancers. METHODS For this first-in-human, single-centre, phase 1 trial, patients aged 18-70 years with a diagnosis of metastatic gastrointestinal epithelial cancer with progressive disease following at least one first line standard therapy, measurable disease with at least one lesion identified as resectable for TIL generation and at least one other lesion meeting RECIST criteria as measurable to serve as an indicator of disease response, and an ECOG performance status of 0 or 1 were screened and enrolled if meeting these and all other eligibility criteria. TILs procured from tumour biopsies were expanded on the basis of neoantigen reactivity, subjected to CRISPR-Cas9-mediated CISH knockout, and infused intravenously into 12 patients after non-myeloablative lymphocyte depleting chemotherapy (cyclophosphamide 60 mg/kg per dose on study days -6 and -5, and fludarabine 25 mg/m2 per dose on days -7 to -3) followed by high-dose IL-2 (aldesleukin; 720 000 IU/kg per dose). The primary endpoint was safety of administration of neoantigen-reactive TILs with knockout of the CISH gene, and a key secondary endpoint was anti-tumour activity measured as objective radiographic response and progression-free and overall survival. This study is registered with ClinicalTrials.gov, NCT04426669, and is complete. FINDINGS Between May 12, 2020, and Sept 16, 2022, 22 participants were enrolled in the trial (one patient was enrolled twice owing to lack of TIL outgrowth on the first attempt); ten patients were female, and 11 were male (self-defined). One patient was Asian, the remainder were White (self-defined). We successfully manufactured CISH knockout TIL products for 19 (86%) of the patients, of whom 12 (63%) received autologous CISH knockout TIL infusion. The median follow-up time for the study was 129 days (IQR 15-283). All 12 (100%) patients had treatment-related severe adverse events. The most common grade 3-4 adverse events included haematological events (12 patients [100%]) attributable to the preparative lymphodepleting chemotherapy regimen or expected effects of IL-2, fatigue (four patients [33%]), and anorexia (three patients [25%]). Deaths of any cause for patients on study were attributed to the underlying disease under study (metastatic gastrointestinal cancer) and related complications (10 patients) or infection (grade 5 septicaemia in one patient). There were no severe (≥grade 3) cytokine release or neurotoxicity events. Six (50%) of 12 patients had stable disease by day 28, and four (33%) had stable disease ongoing at 56 days. One young adult patient with microsatellite-instability-high colorectal cancer refractory to anti-PD1/CTLA-4 therapies had a complete and ongoing response (>21 months). INTERPRETATION These results support the safety and potential antitumour activity of inhibiting the immune checkpoint CISH through the administration of neoantigen-reactive CISH-knockout TILs, with implications for patients with advanced metastatic cancers refractory to checkpoint inhibitor immunotherapies, and provide the first evidence that a novel intracellular checkpoint can be targeted with therapeutic effect. FUNDING Intima Bioscience.
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Affiliation(s)
- Emil Lou
- Department of Medicine, Division of Hematology, Oncology, and Transplantation, University of Minnesota, Minneapolis, MN, USA.
| | | | - Timothy K Starr
- Department of Obstetrics, Gynecology, and Women's Health, University of Minnesota, Minneapolis, MN, USA
| | - Timothy D Folsom
- Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA; Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA; Center for Genome Engineering, University of Minnesota, Minneapolis, MN, USA
| | - Jason Bell
- Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA; Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA; Center for Genome Engineering, University of Minnesota, Minneapolis, MN, USA
| | - Blaine Rathmann
- Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA; Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA; Center for Genome Engineering, University of Minnesota, Minneapolis, MN, USA
| | - Anthony P DeFeo
- Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA; Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA; Center for Genome Engineering, University of Minnesota, Minneapolis, MN, USA
| | - Jihyun Kim
- Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA; Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA; Center for Genome Engineering, University of Minnesota, Minneapolis, MN, USA
| | - Nicholas Slipek
- Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA; Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA; Center for Genome Engineering, University of Minnesota, Minneapolis, MN, USA
| | - Zhaohui Jin
- Deparment of Medical Oncology, Mayo Clinic, Rochester, MN, USA
| | - Darin Sumstad
- Cell Therapy Clinical Laboratory, University of Minnesota Medical School, Minneapolis, MN, USA
| | - Christopher A Klebanoff
- Department of Medicine, Human Oncology and Pathogenesis Program, and Parker Institute for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Katherine Ladner
- Department of Medicine, Division of Hematology, Oncology, and Transplantation, University of Minnesota, Minneapolis, MN, USA
| | - Akshat Sarkari
- Department of Medicine, Division of Hematology, Oncology, and Transplantation, University of Minnesota, Minneapolis, MN, USA
| | - R Scott McIvor
- Department of Genetics, Cell Biology, and Development, University of Minnesota, Minneapolis, MN, USA
| | - Thomas A Murray
- Division of Biostatistics and Health Data Science, University of Minnesota Medical School, Minneapolis, MN, USA
| | - Jeffrey S Miller
- Department of Medicine, Division of Hematology, Oncology, and Transplantation, University of Minnesota, Minneapolis, MN, USA; Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA
| | - Madhuri Rao
- Department of Surgery, University of Minnesota Medical School, Minneapolis, MN, USA
| | - Eric Jensen
- Department of Surgery, University of Minnesota Medical School, Minneapolis, MN, USA
| | - Jacob Ankeny
- Department of Surgery, University of Minnesota Medical School, Minneapolis, MN, USA
| | - Mahmoud A Khalifa
- Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis, MN, USA
| | - Anil Chauhan
- Department of Radiology, University of Kansas Medical Center, Kansas City, KS, USA
| | - Benjamin Spilseth
- Department of Radiology, University of Minnesota Medical School, Minneapolis, MN, USA
| | - Ajay Dixit
- Department of Biomedical Engineering, University of Minnesota, Minneapolis, MN, USA; Division of Gastroenterology, Hepatology, and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - Paolo P Provenzano
- Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA; Department of Biomedical Engineering, University of Minnesota, Minneapolis, MN, USA; Center for Multiparametric Imaging of Tumor Immune Microenvironments, University of Minnesota, Minneapolis, MN, USA; Stem Cell Institute, University of Minnesota, Minneapolis, MN, USA
| | | | | | | | | | - David H McKenna
- Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA; Cell Therapy Clinical Laboratory, University of Minnesota Medical School, Minneapolis, MN, USA
| | - Matthew J Johnson
- Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA; Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA; Center for Genome Engineering, University of Minnesota, Minneapolis, MN, USA
| | - Beau R Webber
- Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA; Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA; Center for Genome Engineering, University of Minnesota, Minneapolis, MN, USA
| | - Branden S Moriarity
- Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA; Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA; Center for Genome Engineering, University of Minnesota, Minneapolis, MN, USA
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3
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Wu X, Yang Q, Leng L, Yang P, Zhu Z. Altered metabolic profiles in colon and rectal cancer. Sci Rep 2025; 15:11310. [PMID: 40175601 PMCID: PMC11965280 DOI: 10.1038/s41598-025-96004-8] [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: 04/10/2024] [Accepted: 03/25/2025] [Indexed: 04/04/2025] Open
Abstract
Colorectal cancer (CRC) is the third most commonly diagnosed malignant tumour in worldwide populations. Although colon cancer (CC) and rectal cancer (RC) are often discussed together, there is a global trend towards considering them as two separate disease entities. It is necessary to choice the appropriate treatment for CC and RC based on their own characteristics. Hence, it is a great importance to find effective biomarkers to distinguish CC from RC. In the present study, a total of 343 participants were recruited, including 132 healthy individuals, 101 patients with CC, and 110 patients with RC. The concentrations of 93 metabolites were determined by using a combination of dried blood spot sampling and direct infusion mass spectrometry technology. Multiple algorithms were applied to characterize altered metabolic profiles in CC and RC. Significantly altered metabolites were screened for distinguishing RC from CC in training set. A biomarker panel including Glu, C0, C8, C20, Gly/Ala, and C10:1 was tested with tenfold cross-validation and an independent test set, and showed the potential to distinguish between RC and CC. The metabolomics analysis makes contribution to summarize the metabolic differences in RC and CC, which might provide further guidance on novel clinical designs for the two diseases.
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Affiliation(s)
- Xue Wu
- Guizhou University of Traditional Chinese Medicine, Guiyang, 550025, Guizhou, China
- The Second Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Guiyang, 550003, Guizhou, China
| | - Qi Yang
- Guizhou University of Traditional Chinese Medicine, Guiyang, 550025, Guizhou, China
- The Second Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Guiyang, 550003, Guizhou, China
| | - Li Leng
- Guizhou University of Traditional Chinese Medicine, Guiyang, 550025, Guizhou, China
- The Second Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Guiyang, 550003, Guizhou, China
| | - Peng Yang
- Guizhou University of Traditional Chinese Medicine, Guiyang, 550025, Guizhou, China.
- The Second Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Guiyang, 550003, Guizhou, China.
| | - Zhitu Zhu
- Liaoning Provincial Key Laboratory of Clinical Oncology Metabonomics, Jinzhou Medical University, Jinzhou, China.
- The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, 121000, Liaoning, China.
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Sharma S, Singh N, Turk AA, Wan I, Guttikonda A, Dong JL, Zhang X, Opyrchal M. Molecular insights into clinical trials for immune checkpoint inhibitors in colorectal cancer: Unravelling challenges and future directions. World J Gastroenterol 2024; 30:1815-1835. [PMID: 38659481 PMCID: PMC11036501 DOI: 10.3748/wjg.v30.i13.1815] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2023] [Revised: 02/22/2024] [Accepted: 03/13/2024] [Indexed: 04/03/2024] Open
Abstract
Colorectal cancer (CRC) is a complex disease with diverse etiologies and clinical outcomes. Despite considerable progress in development of CRC therapeutics, challenges remain regarding the diagnosis and management of advanced stage metastatic CRC (mCRC). In particular, the five-year survival rate is very low since mCRC is currently rarely curable. Over the past decade, cancer treatment has significantly improved with the introduction of cancer immunotherapies, specifically immune checkpoint inhibitors. Therapies aimed at blocking immune checkpoints such as PD-1, PD-L1, and CTLA-4 target inhibitory pathways of the immune system, and thereby enhance anti-tumor immunity. These therapies thus have shown promising results in many clinical trials alone or in combination. The efficacy and safety of immunotherapy, either alone or in combination with CRC, have been investigated in several clinical trials. Clinical trials, including KEYNOTE-164 and CheckMate 142, have led to Food and Drug Administration approval of the PD-1 inhibitors pembrolizumab and nivolumab, respectively, for the treatment of patients with unresectable or metastatic microsatellite instability-high or deficient mismatch repair CRC. Unfortunately, these drugs benefit only a small percentage of patients, with the benefits of immunotherapy remaining elusive for the vast majority of CRC patients. To this end, primary and secondary resistance to immunotherapy remains a significant issue, and further research is necessary to optimize the use of immunotherapy in CRC and identify biomarkers to predict the response. This review provides a comprehensive overview of the clinical trials involving immune checkpoint inhibitors in CRC. The underlying rationale, challenges faced, and potential future steps to improve the prognosis and enhance the likelihood of successful trials in this field are discussed.
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Affiliation(s)
- Samantha Sharma
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, United States
| | - Naresh Singh
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, United States
| | - Anita Ahmed Turk
- Division of Hematology/Oncology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, United States
| | - Isabella Wan
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, United States
| | - Akshay Guttikonda
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, United States
| | - Julia Lily Dong
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, United States
| | - Xinna Zhang
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, United States
- Melvin and Bren Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, IN 46202, United States
| | - Mateusz Opyrchal
- Division of Hematology/Oncology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, United States
- Melvin and Bren Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, IN 46202, United States
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Zhou X, Li D, Xia S, Ma X, Li R, Mu Y, Liu Z, Zhang L, Zhou Q, Zhuo W, Ding K, Lin A, Liu W, Liu X, Zhou T. RNA-based modulation of macrophage-mediated efferocytosis potentiates antitumor immunity in colorectal cancer. J Control Release 2024; 366:128-141. [PMID: 38104775 DOI: 10.1016/j.jconrel.2023.12.018] [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: 09/29/2023] [Revised: 11/28/2023] [Accepted: 12/12/2023] [Indexed: 12/19/2023]
Abstract
Tumor-associated macrophages play pivotal roles in tumor progression and metastasis. Macrophage-mediated clearance of apoptotic cells (efferocytosis) supports inflammation resolution, contributing to immune evasion in colorectal cancers. To reverse this immunosuppressive process, we propose a readily translatable RNA therapy to selectively inhibit macrophage-mediated efferocytosis in tumor microenvironment. A clinically approved lipid nanoparticle platform (LNP) is employed to encapsulate siRNA for the phagocytic receptor MerTK (siMerTK), enabling selective MerTK inhibition in the diseased organ. Decreased MerTK expression in tumor-associated macrophages results in apoptotic cell accumulation and immune activation in tumor microenvironment, leading to suppressed tumor growth and better survival in both liver and peritoneal metastasis models of colorectal cancers. siMerTK delivery combined with PD-1 blockade further produces enhanced antimetastatic efficacy with reactivated intratumoral immune milieu. Collectively, LNP-based siMerTK delivery combined with immune checkpoint therapy may present a feasible modality for metastatic colorectal cancer therapy.
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Affiliation(s)
- Xuefei Zhou
- International Institutes of Medicine, The Fourth Affiliated Hospital of Zhejiang University School of Medicine, Yiwu 322000, China.
| | - Dezhi Li
- Department of Oncology, The Fourth Affiliated Hospital of Zhejiang University School of Medicine, Yiwu 322000, China
| | - Shenglong Xia
- Department of Gastroenterology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310009, China; Cancer Center, Zhejiang University, Hangzhou 310058, China
| | - Xixi Ma
- Department of Cell Biology, Zhejiang University School of Medicine, Hangzhou 310058, China; Center for Medical Research and Innovation in Digestive System Tumors, Ministry of Education, Hangzhou, Zhejiang 310020, China
| | - Rong Li
- Department of Pharmacology, Zhejiang University School of Medicine, Hangzhou 310058, China
| | - Yongli Mu
- Department of Cell Biology, Zhejiang University School of Medicine, Hangzhou 310058, China
| | - Zimo Liu
- Department of Cell Biology, Zhejiang University School of Medicine, Hangzhou 310058, China
| | - Lu Zhang
- Department of Cell Biology, Zhejiang University School of Medicine, Hangzhou 310058, China
| | - Quan Zhou
- Department of Cell Biology, Zhejiang University School of Medicine, Hangzhou 310058, China
| | - Wei Zhuo
- Department of Cell Biology, Zhejiang University School of Medicine, Hangzhou 310058, China
| | - Kefeng Ding
- Center for Medical Research and Innovation in Digestive System Tumors, Ministry of Education, Hangzhou, Zhejiang 310020, China
| | - Aifu Lin
- College of Life Sciences, Zhejiang University, Hangzhou 310058, China
| | - Wei Liu
- International Institutes of Medicine, The Fourth Affiliated Hospital of Zhejiang University School of Medicine, Yiwu 322000, China
| | - Xiangrui Liu
- Department of Gastroenterology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310009, China; Cancer Center, Zhejiang University, Hangzhou 310058, China; Department of Pharmacology, Zhejiang University School of Medicine, Hangzhou 310058, China; Innovation Center of Yangtze River Delta, Zhejiang University, Jiaxing 314100, China.
| | - Tianhua Zhou
- Cancer Center, Zhejiang University, Hangzhou 310058, China; Department of Cell Biology, Zhejiang University School of Medicine, Hangzhou 310058, China; Center for Medical Research and Innovation in Digestive System Tumors, Ministry of Education, Hangzhou, Zhejiang 310020, China.
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Yang LP, Jiang TJ, He MM, Ling YH, Wang ZX, Wu HX, Zhang Z, Xu RH, Wang F, Yuan SQ, Zhao Q. Comprehensive genomic characterization of sporadic synchronous colorectal cancer: Implications for treatment optimization and clinical outcome. Cell Rep Med 2023; 4:101222. [PMID: 37794586 PMCID: PMC10591049 DOI: 10.1016/j.xcrm.2023.101222] [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: 01/17/2023] [Revised: 07/12/2023] [Accepted: 09/11/2023] [Indexed: 10/06/2023]
Abstract
Sporadic synchronous colorectal cancer (SCRC) refers to multiple primary CRC tumors detected simultaneously in an individual without predisposing hereditary conditions, which accounts for the majority of multiple CRCs while lacking a profound understanding of the genomic landscape and evolutionary dynamics to optimize its treatment. In this study, 103 primary tumor samples from 51 patients with SCRC undergo whole-exome sequencing. The germline and somatic mutations and evolutionary and clinical features are comprehensively investigated. Somatic genetic events are largely inconsistent between paired tumors. Compared with solitary CRC, SCRCs have higher prevalence of tumor mutation burden high (TMB-H; 33.3%) and microsatellite-instability high (MSI-H; 29.4%) and different mutation frequencies in oncogenic signaling pathways. Moreover, neutrally evolving SCRC tumors are associated with higher intratumoral heterogeneity and better prognosis. These findings unveil special molecular features, carcinogenesis, and prognosis of sporadic SCRC. Strategies for targeted therapy and immunotherapy should be optimized accordingly.
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Affiliation(s)
- Lu-Ping Yang
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, P.R. China
| | - Teng-Jia Jiang
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, P.R. China
| | - Ming-Ming He
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, P.R. China; Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences, Guangzhou 510060, P.R. China
| | - Yi-Hong Ling
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, P.R. China
| | - Zi-Xian Wang
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, P.R. China; Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences, Guangzhou 510060, P.R. China
| | - Hao-Xiang Wu
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, P.R. China; Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences, Guangzhou 510060, P.R. China
| | - Zhen Zhang
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, P.R. China
| | - Rui-Hua Xu
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, P.R. China; Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences, Guangzhou 510060, P.R. China
| | - Feng Wang
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, P.R. China
| | - Shu-Qiang Yuan
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, P.R. China.
| | - Qi Zhao
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, P.R. China.
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7
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Ozer M, Vegivinti CTR, Syed M, Ferrell ME, Gonzalez Gomez C, Cheng S, Holder-Murray J, Bruno T, Saeed A, Sahin IH. Neoadjuvant Immunotherapy for Patients with dMMR/MSI-High Gastrointestinal Cancers: A Changing Paradigm. Cancers (Basel) 2023; 15:3833. [PMID: 37568648 PMCID: PMC10417711 DOI: 10.3390/cancers15153833] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2023] [Revised: 07/19/2023] [Accepted: 07/25/2023] [Indexed: 08/13/2023] Open
Abstract
Immune checkpoint inhibitors have revolutionized the management of mismatch repair-deficient (MMR-D)/microsatellite instability-high (MSI-H) gastrointestinal cancers, particularly colorectal cancer. Cancers with the MMR-D/MSI-H genotype often carry a higher tumor mutation burden with frameshift alterations, leading to increased mutation-associated neoantigen (MANA) generation. The dramatic response seen with immune checkpoint inhibitors (ICIs), which are orchestrated by MANA-primed effector T cells, resulted in the rapid development of these novel therapeutics within the landscape of MSI-H gastrointestinal cancers. Recently, several clinical trials have utilized ICIs as potential neoadjuvant therapies for MSI-H gastrointestinal cancers and demonstrated deep clinical and pathological responses, creating opportunities for organ preservation. However, there are potential challenges to the neoadjuvant use of ICIs for certain disease types due to the clinical risk of overtreatment for a disease that can be cured through a surgery-only approach. In this review article, we discuss neoadjuvant management approaches with ICI therapy for patients with MSI-H gastrointestinal cancers, including those with oligometastatic disease. We also elaborate on potential challenges and opportunities for the neoadjuvant utilization of ICIs and provide further insight into the changing treatment paradigm of MMR-D/MSI-H gastrointestinal cancers.
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Affiliation(s)
- Muhammet Ozer
- Department of Gastrointestinal Oncology, Dana Farber Cancer Institute, Boston, MA 02215, USA
| | | | - Masood Syed
- Department of Medicine, University of Pittsburg School of Medicine, Pittsburgh, PA 15213, USA
| | - Morgan E. Ferrell
- Department of Medicine, University of Pittsburg School of Medicine, Pittsburgh, PA 15213, USA
| | - Cyndi Gonzalez Gomez
- Department of Medicine, University of Pittsburg School of Medicine, Pittsburgh, PA 15213, USA
| | - Svea Cheng
- Department of Medicine, University of Pittsburg School of Medicine, Pittsburgh, PA 15213, USA
| | - Jennifer Holder-Murray
- Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
| | - Tullia Bruno
- Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
| | - Anwaar Saeed
- Division of Hematology/Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
| | - Ibrahim Halil Sahin
- Division of Hematology/Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
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8
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Kalaei Z, Manafi-Farid R, Rashidi B, Kiani FK, Zarei A, Fathi M, Jadidi-Niaragh F. The Prognostic and therapeutic value and clinical implications of fibroblast activation protein-α as a novel biomarker in colorectal cancer. Cell Commun Signal 2023; 21:139. [PMID: 37316886 DOI: 10.1186/s12964-023-01151-y] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2022] [Accepted: 04/28/2023] [Indexed: 06/16/2023] Open
Abstract
The identification of contributing factors leading to the development of Colorectal Cancer (CRC), as the third fatal malignancy, is crucial. Today, the tumor microenvironment has been shown to play a key role in CRC progression. Fibroblast-Activation Protein-α (FAP) is a type II transmembrane cell surface proteinase expressed on the surface of cancer-associated fibroblasts in tumor stroma. As an enzyme, FAP has di- and endoprolylpeptidase, endoprotease, and gelatinase/collagenase activities in the Tumor Microenvironment (TME). According to recent reports, FAP overexpression in CRC contributes to adverse clinical outcomes such as increased lymph node metastasis, tumor recurrence, and angiogenesis, as well as decreased overall survival. In this review, studies about the expression level of FAP and its associations with CRC patients' prognosis are reviewed. High expression levels of FAP and its association with clinicopathological factors have made as a potential target. In many studies, FAP has been evaluated as a therapeutic target and diagnostic factor into which the current review tries to provide a comprehensive insight. Video Abstract.
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Affiliation(s)
- Zahra Kalaei
- Department of Biology, Faculty of Natural Sciences, Tabriz University, Tabriz, Iran
| | - Reyhaneh Manafi-Farid
- Research Center for Nuclear Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Bentolhoda Rashidi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Fariba Karoon Kiani
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Asieh Zarei
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mehrdad Fathi
- Research Center for Integrative Medicine in Aging, Aging Research Institute, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Farhad Jadidi-Niaragh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
- Research Center for Integrative Medicine in Aging, Aging Research Institute, Tabriz University of Medical Sciences, Tabriz, Iran.
- Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
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9
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Meyiah A, Mahmoodi Chalbatani G, Al-Mterin MA, Malekraeisi MA, Murshed K, Elkord E. Co-expression of PD-1 with TIGIT or PD-1 with TIM-3 on tumor-infiltrating CD8 + T cells showed synergistic effects on improved disease-free survival in treatment-naïve CRC patients. Int Immunopharmacol 2023; 119:110207. [PMID: 37099940 DOI: 10.1016/j.intimp.2023.110207] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2023] [Revised: 04/11/2023] [Accepted: 04/14/2023] [Indexed: 04/28/2023]
Abstract
Immune checkpoints (ICs) are highly expressed on tumor-infiltrating immune cells (TIICs) in different malignancies, including colorectal cancer (CRC). T cells play crucial roles in shaping CRC, and their presence in the tumor microenvironment (TME) has proven to be one of the best predictors of clinical outcomes. A crucial component of the immune system is cytotoxic CD8+ T cells (CTLs), which play decisive roles in the prognosis of CRC. In this study, we investigated associations of immune checkpoints expressed on tumor-infiltrating CD8+ T cells with disease-free survival (DFS) in 45 naïve-treatment CRC patients. First, we examined the associations of single ICs, and found that CRC patients with higher levels of T-cell immunoglobulin and ITIM-domain (TIGIT), T-cell immunoglobulin and mucin domain-3 (TIM-3) and programmed cell death-1 (PD-1) CD8+ T cells tended to have longer DFS. Interestingly, when PD-1 expression was combined with other ICs, there were more evident and stronger associations between higher levels of PD-1+ with TIGIT+ or PD-1+ with TIM-3+ tumor-infiltrating CD8+ T cells and longer DFS. Our findings for TIGIT were validated in The Cancer Genome Atlas (TCGA) CRC dataset. This study is the first to report on the association of co-expression of PD-1 with TIGIT and PD-1 with TIM-3 in CD8+ T cells and improved DFS in treatment-naïve CRC patients. This work highlights the significance of immune checkpoint expression on tumor-infiltrating CD8+ T cells as critical predictive biomarkers, especially when co-expression of different ICs is considered.
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Affiliation(s)
- Abdo Meyiah
- Natural and Medical Sciences Research Center, University of Nizwa, Nizwa 616, Oman
| | | | - Mohamed A Al-Mterin
- Natural and Medical Sciences Research Center, University of Nizwa, Nizwa 616, Oman
| | | | - Khaled Murshed
- Department of Pathology, Hamad Medical Corporation, Doha, Qatar
| | - Eyad Elkord
- Natural and Medical Sciences Research Center, University of Nizwa, Nizwa 616, Oman; Department of Biological Sciences and Chemistry, Faculty of Arts and Sciences, University of Nizwa, Nizwa 616, Oman; Biomedical Research Center, School of Science, Engineering and Environment, University of Salford, Manchester, UK.
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10
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San-Román-Gil M, Torres-Jiménez J, Pozas J, Esteban-Villarrubia J, Albarrán-Fernández V, Álvarez-Ballesteros P, Chamorro-Pérez J, Rosero-Rodríguez D, Orejana-Martín I, Martínez-Delfrade Í, Reguera-Puertas P, Fuentes-Mateos R, Ferreiro-Monteagudo R. Current Landscape and Potential Challenges of Immune Checkpoint Inhibitors in Microsatellite Stable Metastatic Colorectal Carcinoma. Cancers (Basel) 2023; 15:863. [PMID: 36765821 PMCID: PMC9913409 DOI: 10.3390/cancers15030863] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Revised: 01/25/2023] [Accepted: 01/27/2023] [Indexed: 01/31/2023] Open
Abstract
Colorectal cancer (CRC) is the third most frequent cancer and the second most common cause of cancer-related death in Europe. High microsatellite instability (MSI-H) due to a deficient DNA mismatch repair (dMMR) system can be found in 5% of metastatic CRC (mCRC) and has been established as a biomarker of response to immunotherapy in these tumors. Therefore, immune checkpoint inhibitors (ICIs) in mCRC with these characteristics were evaluated with results showing remarkable response rates and durations of response. The majority of mCRC cases have high levels of DNA mismatch repair proteins (pMMR) with consequent microsatellite stability or low instability (MSS or MSI-low), associated with an inherent resistance to ICIs. This review aims to provide a comprehensive analysis of the possible approaches to overcome the mechanisms of resistance and evaluates potential biomarkers to establish the role of ICIs in pMMR/MSS/MSI-L (MSS) mCRC.
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Affiliation(s)
- María San-Román-Gil
- Medical Oncology Department, Ramón y Cajal University Hospital, 28034 Madrid, Spain
| | - Javier Torres-Jiménez
- Medical Oncology Department, Clínico San Carlos University Hospital, 28040 Madrid, Spain
| | - Javier Pozas
- Medical Oncology Department, Ramón y Cajal University Hospital, 28034 Madrid, Spain
| | | | | | | | - Jesús Chamorro-Pérez
- Medical Oncology Department, Ramón y Cajal University Hospital, 28034 Madrid, Spain
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11
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Zhou L, Yang XQ, Zhao GY, Wang FJ, Liu X. Meta-analysis of neoadjuvant immunotherapy for non-metastatic colorectal cancer. Front Immunol 2023; 14:1044353. [PMID: 36776899 PMCID: PMC9911889 DOI: 10.3389/fimmu.2023.1044353] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2022] [Accepted: 01/16/2023] [Indexed: 01/28/2023] Open
Abstract
Background Immunotherapy has been approved for the treatment of metastatic colorectal cancer. The efficacy and safety of neoadjuvant immunotherapy for the treatment of non-metastatic colorectal cancer remains unclear. We tried to explore clinical effect of neoadjuvant immunotherapy in the treatment of non-metastatic colorectal cancer. Methods We searched the databases (PubMed, Wanfang Embase, Cochrane Library and China National Knowledge Infrastructure databases) to obtain suitable articles up to September 2022. The primary outcomes of pathological complete response (pCRs), major pathological response (MPR), objective response rate (ORR), R0-resection and anus preserving rate were collected and evaluated. Secordary outcomes (pCRs and MPR) of subgroup analysis between deficient mismatch repair/microsatellite instability-high group (dMMR/MSI-H) and proficient mismatch repair/microsatellite stable group (pMMR/MSS) and outcomes for rectal cancer were analyzed for the final results. Results We included ten articles and 410 cases of non-metastatic colorectal cancer with neoadjuvant immunotherapy. There were 113 (27.5%) cases with the dMMR/MSI-H status and 167 (40.7%) cases with the pMMR/MSS status. pCRs was found in 167/373 (44.6%) patients (ES: 0.49, 95% CI: 0.36 to 0.62, P<0.01, chi2 = 65.3, P<0.01, I 2 = 86.2%) and MPR was found in 194/304 (63.8%) patients (ES: 0.66, 95% CI: 0.54 to 0.78, P<0.01, chi2 = 42.55, P<0.01, I 2 = 81.2%) with the random-effects model and huge heterogeneity. In the subgroup analysis, pCRs was higher in the dMMR/MSI-H group than the pMMR/MSS group in the fixed-effects model with minimal heterogeneity (OR: 3.55, 95% CI: 1.74 to 7.27, P<0.01, chi2 = 1.86, P=0.6, I 2 = 0%). pCRs was found in 58/172 (33.9%) rectal cancer patients (ES: 0.33, 95% CI: 0.26 to 0.40, P<0.01, chi2 = 3.04, P=0.55, I 2 = 0%) with the fixed-effects model and little heterogeneity. Conclusion Neoadjuvant immunotherapy could increase pCRs and MPR rate for non-metastatic colorectal cancer. Neoadjuvant immunotherapy could achieve better pCRs rate in dMMR/MSI-H group than in the pMMR/MSS group. Neoadjuvant immunotherapy could be another treatment option for non-metastatic colorectal cancer. Systematic review registration https://www.crd.york.ac.uk/prospero/#myprospero, identifier CRD42022350523.
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Affiliation(s)
- Long Zhou
- Department of Orthopedics, Shengjing Hospital of China Medical University, Shenyang, China
| | - Xiao-Quan Yang
- Department of General Surgery, Liaoning Cancer Hospital & Institute, Cancer Hospital of China Medical University, Shenyang, Liaoning, China
| | - Guang-yue Zhao
- Department of Colorectal Surgery, Liaoning Cancer Hospital & Institute, Cancer Hospital of China Medical University, Shenyang, Liaoning, China
| | - Feng-jian Wang
- Department of Colorectal Surgery, Liaoning Cancer Hospital & Institute, Cancer Hospital of China Medical University, Shenyang, Liaoning, China
| | - Xin Liu
- Department of Colorectal Surgery, Liaoning Cancer Hospital & Institute, Cancer Hospital of China Medical University, Shenyang, Liaoning, China,*Correspondence: Xin Liu,
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12
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Yu I, Dakwar A, Takabe K. Immunotherapy: Recent Advances and Its Future as a Neoadjuvant, Adjuvant, and Primary Treatment in Colorectal Cancer. Cells 2023; 12:cells12020258. [PMID: 36672193 PMCID: PMC9856401 DOI: 10.3390/cells12020258] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2022] [Revised: 01/02/2023] [Accepted: 01/04/2023] [Indexed: 01/10/2023] Open
Abstract
Immunotherapy in colorectal cancer (CRC) has made great strides within the past decade. Immune checkpoint inhibitors are a class of immunotherapy and have been shown to greatly improve patient outcomes in mismatch repair-deficient (dMMR) CRC. Now, they are part of the standard of care for this subset of CRC. Because of this, there has been a growing interest in the efficacy and timing of immunotherapy for other subsets of CRC, including locally advanced, metastatic, and microsatellite stable (MSS). In this review, we aim to examine the three main classes of immunotherapy for CRC-immune checkpoint inhibitors (ICIs), adoptive cell transfer therapy (ACT), and tumor vaccines-and discuss the most recent advances and future directions for each.
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Affiliation(s)
- Irene Yu
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA
- Department of Surgery, Jacobs School of Medicine and Biomedical Sciences, State University of New York, Buffalo, NY 14214, USA
| | - Anthony Dakwar
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA
- Department of Surgery, Jacobs School of Medicine and Biomedical Sciences, State University of New York, Buffalo, NY 14214, USA
| | - Kazuaki Takabe
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA
- Department of Surgery, Jacobs School of Medicine and Biomedical Sciences, State University of New York, Buffalo, NY 14214, USA
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan
- Department of Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan
- Department of Breast Surgery and Oncology, Tokyo Medical University, Tokyo 160-8402, Japan
- Department of Breast Surgery, Fukushima Medical University, Fukushima 960-1295, Japan
- Correspondence: ; Tel.: +1-716-845-5128
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13
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Frederico SC, Darling C, Bielanin JP, Dubinsky AC, Zhang X, Hadjipanayis CG, Kohanbash G. Neoadjuvant immune checkpoint inhibition in the management of glioblastoma: Exploring a new frontier. Front Immunol 2023; 14:1057567. [PMID: 36875096 PMCID: PMC9981631 DOI: 10.3389/fimmu.2023.1057567] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Accepted: 02/03/2023] [Indexed: 02/19/2023] Open
Abstract
Brain tumors are one of the leading causes of cancer related death in both the adult and pediatric patient population. Gliomas represent a cohort of brain tumors derived from glial cell lineages which include astrocytomas, oligodendrogliomas and glioblastomas (GBMs). These tumors are known to grow aggressively and have a high lethality with GBM being the most aggressive tumor in this group. Currently, few treatment options exist for GBM outside of surgical resection, radiation therapy and chemotherapy. While these measures have been shown to marginally improve patient survival, patients, especially those diagnosed with GBM, often experience a recurrence of their disease. Following disease recurrence, treatment options become more limited as additional surgical resections can pose life threatening risk to the patient, patients may be ineligible for additional radiation, and the recurrent tumor may be resistant to chemotherapy. Immune checkpoint inhibitors (ICIs) have revolutionized the field of cancer immunotherapy as many patients with cancers residing outside the central nervous system (CNS) have experienced a survival benefit from this treatment modality. It has often been observed that this survival benefit is increased following neoadjuvant administration of immune checkpoint inhibitors as tumor antigen is still present in the patient which enables a more robust anti-tumor immune response. Interestingly, results for ICI-based studies for patients with GBM have been largely disappointing which is a stark contrast from the success this treatment modality has had in non-central nervous system cancers. In this review, we will discuss the various benefits of neoadjuvant immune checkpoint inhibition such as how this approach reduces tumor burden and allows for a greater induction of an anti-tumor immune response. Additionally, we will discuss several non-CNS cancers where neoadjuvant immune checkpoint inhibition has been successful and discuss why we believe this approach may provide a survival benefit for GBM patients. We hope this manuscript will foster future studies aimed at exploring whether this approach may be beneficial for patients diagnosed with GBM.
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Affiliation(s)
- Stephen C Frederico
- University of Pittsburgh School of Medicine, Pittsburgh, PA, United States.,Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, PA, United States
| | - Corbin Darling
- University of Pittsburgh School of Medicine, Pittsburgh, PA, United States.,Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, PA, United States
| | - John P Bielanin
- University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
| | | | - Xiaoran Zhang
- Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, PA, United States
| | | | - Gary Kohanbash
- Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, PA, United States
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14
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Jiang G, Wu Q, Li B. Evaluation of immunotherapy efficacy in gynecologic cancer. Front Immunol 2023; 14:1061761. [PMID: 36793735 PMCID: PMC9922993 DOI: 10.3389/fimmu.2023.1061761] [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: 10/05/2022] [Accepted: 01/16/2023] [Indexed: 01/31/2023] Open
Abstract
Various immunotherapies have demonstrated remarkable success over the past few decades, and have been approved for the treatment of different cancer types. However, patient responses to immunotherapy are variable, and approximately 50% of cases are refractory to these agents. Tumor biomarker-based stratification of cases may therefore help identify subpopulations that are sensitive/resistant to immunotherapy; it may also improve prediction of response in various cancers including gynecologic cancer. These biomarkers include the tumor mutational burden, microsatellite instability, mismatch repair deficiency, T cell-inflamed gene expression profile, programmed cell death protein 1 ligand 1, tumor-infiltrating lymphocytes, and numerous other genomic alterations. Future directions in the treatment of gynecologic cancer include the utilization of these biomarkers to select ideal candidates. This review focused on recent advances in the predictive ability of molecular biomarkers in patients with gynecologic cancer who undergo immunotherapy. The most recent developments in combined immunotherapy and targeted therapy strategies and novel immune interventions against gynecologic cancers have also been discussed.
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Affiliation(s)
- Genyi Jiang
- Department of Gynecology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Qianhua Wu
- School of Medicine, Tongji University, Shanghai, China
| | - Bilan Li
- Department of Gynecology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, China
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15
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Prakash A, Gates T, Zhao X, Wangmo D, Subramanian S. Tumor-derived extracellular vesicles in the colorectal cancer immune environment and immunotherapy. Pharmacol Ther 2023; 241:108332. [PMID: 36526013 DOI: 10.1016/j.pharmthera.2022.108332] [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: 09/07/2022] [Revised: 12/06/2022] [Accepted: 12/12/2022] [Indexed: 12/15/2022]
Abstract
Despite significant advances in the screening, diagnosis, and treatment of colorectal cancer (CRC) immune checkpoint inhibitors (ICIs) continue to have limited utility outside of microsatellite-high disease. Given the durable response to immunotherapy seen across malignancies, increasing CRC response rates to ICI therapy is an active area of clinical research. An increasing body of work has demonstrated that tumor-derived extracellular vesicles (TEVs) are key modulators in tumor signaling and the determinants of the tumor microenvironment. Pre-clinical models have shown that TEVs are directly involved in antigen presentation and are involved in radiation-induced DNA damage signaling. Both direct and indirect modifications of these TEVs can alter CRC immunogenicity and ICI treatment response, making them attractive targets for potential therapeutic development. In addition, modified TEVs can be developed using several different mechanisms, with varied cargo including micro-RNAs and small peptide molecules. Recent work has shown strong pre-clinical evidence of injected modified TEV-induced ICI activity, with knockdown of the micro-RNA miR-424 in TEVs improving CRC immunogenicity and increasing anti-PD-1 activity in mouse models. Clinical trials are ongoing in the evaluation of modified TEVs in cancer therapy, but they appear to be a promising therapeutic target in CRC.
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Affiliation(s)
- Ajay Prakash
- Masonic Cancer Center, University of Minnesota Medical School, Minneapolis, MN, United States of America.
| | - Travis Gates
- Department of Surgery, University of Minnesota Medical School, Minneapolis, MN, United States of America
| | - Xianda Zhao
- Department of Surgery, University of Minnesota Medical School, Minneapolis, MN, United States of America
| | - Dechen Wangmo
- Department of Surgery, University of Minnesota Medical School, Minneapolis, MN, United States of America
| | - Subbaya Subramanian
- Masonic Cancer Center, University of Minnesota Medical School, Minneapolis, MN, United States of America; Department of Surgery, University of Minnesota Medical School, Minneapolis, MN, United States of America; Center for Immunology, University of Minnesota Medical School, Minneapolis, MN, United States of America
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16
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Chen B, Xi Y, Zhao J, Hong Y, Tian S, Zhai X, Chen Q, Ren X, Fan L, Xie X, Jiang C. m5C regulator-mediated modification patterns and tumor microenvironment infiltration characterization in colorectal cancer: One step closer to precision medicine. Front Immunol 2022; 13:1049435. [PMID: 36532062 PMCID: PMC9751490 DOI: 10.3389/fimmu.2022.1049435] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Accepted: 11/09/2022] [Indexed: 12/04/2022] Open
Abstract
Background The RNA modification 5-methylcytosine (m5C) is one of the most prevalent post-transcriptional modifications, with increasing evidence demonstrating its extensive involvement in the tumorigenesis and progression of various cancers. Colorectal cancer (CRC) is the third most common cancer and second leading cause of cancer-related deaths worldwide. However, the role of m5C modulators in shaping tumor microenvironment (TME) heterogeneity and regulating immune cell infiltration in CRC requires further clarification. Results The transcriptomic sequencing data of 18 m5C regulators and clinical data of patients with CRC were obtained from The Cancer Genome Atlas (TCGA) and systematically evaluated. We found that 16 m5C regulators were differentially expressed between CRC and normal tissues. Unsupervised cluster analysis was then performed and revealed two distinct m5C modification patterns that yielded different clinical prognoses and biological functions in CRC. We demonstrated that the m5C score constructed from eight m5C-related genes showed excellent prognostic performance, with a subsequent independent analysis confirming its predictive ability in the CRC cohort. Then we developed a nomogram containing five clinical risk factors and the m5C risk score and found that the m5C score exhibited high prognostic prediction accuracy and favorable clinical applicability. Moreover, the CRC patients with low m5C score were characterized by "hot" TME exhibiting increased immune cell infiltration and higher immune checkpoint expression. These characteristics were highlighted as potential identifiers of suitable candidates for anticancer immunotherapy. Although the high m5C score represented the non-inflammatory phenotype, the CRC patients in this group exhibited high level of sensitivity to molecular-targeted therapy. Conclusion Our comprehensive analysis indicated that the novel m5C clusters and scoring system accurately reflected the distinct prognostic signature, clinicopathological characteristics, immunological phenotypes, and stratifying therapeutic opportunities of CRC. Our findings, therefore, offer valuable insights into factors that may be targeted in the development of precision medicine-based therapeutic strategies for CRC.
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Affiliation(s)
- Baoxiang Chen
- Department of Colorectal and Anal Surgery, Zhongnan Hospital of Wuhan University, Wuhan, China,Clinical Center of Intestinal and Colorectal Diseases of Hubei Province (Zhongnan Hospital of Wuhan University), Wuhan, China,Hubei Key Laboratory of Intestinal and Colorectal Diseases (Zhongnan Hospital of Wuhan University), Wuhan, China
| | - Yiqing Xi
- Department of Breast and Thyroid Surgery, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Jianhong Zhao
- Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan, China,Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Wuhan University, Wuhan, China
| | - Yuntian Hong
- Department of Colorectal and Anal Surgery, Zhongnan Hospital of Wuhan University, Wuhan, China,Clinical Center of Intestinal and Colorectal Diseases of Hubei Province (Zhongnan Hospital of Wuhan University), Wuhan, China,Hubei Key Laboratory of Intestinal and Colorectal Diseases (Zhongnan Hospital of Wuhan University), Wuhan, China
| | - Shunhua Tian
- Department of Colorectal and Anal Surgery, Zhongnan Hospital of Wuhan University, Wuhan, China,Clinical Center of Intestinal and Colorectal Diseases of Hubei Province (Zhongnan Hospital of Wuhan University), Wuhan, China,Hubei Key Laboratory of Intestinal and Colorectal Diseases (Zhongnan Hospital of Wuhan University), Wuhan, China
| | - Xiang Zhai
- Department of Colorectal and Anal Surgery, Zhongnan Hospital of Wuhan University, Wuhan, China,Clinical Center of Intestinal and Colorectal Diseases of Hubei Province (Zhongnan Hospital of Wuhan University), Wuhan, China,Hubei Key Laboratory of Intestinal and Colorectal Diseases (Zhongnan Hospital of Wuhan University), Wuhan, China
| | - Quanjiao Chen
- CAS Key Laboratory of Special Pathogens and Biosafety, CAS Center for Influenza Research and Early Warning, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China
| | - Xianghai Ren
- Department of Colorectal and Anal Surgery, Zhongnan Hospital of Wuhan University, Wuhan, China,Clinical Center of Intestinal and Colorectal Diseases of Hubei Province (Zhongnan Hospital of Wuhan University), Wuhan, China,Hubei Key Laboratory of Intestinal and Colorectal Diseases (Zhongnan Hospital of Wuhan University), Wuhan, China,*Correspondence: Congqing Jiang, ; Xiaoyu Xie, ; Lifang Fan, ; Xianghai Ren,
| | - Lifang Fan
- Department of Pathology, Hubei Cancer Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China,*Correspondence: Congqing Jiang, ; Xiaoyu Xie, ; Lifang Fan, ; Xianghai Ren,
| | - Xiaoyu Xie
- Department of Colorectal and Anal Surgery, Zhongnan Hospital of Wuhan University, Wuhan, China,Clinical Center of Intestinal and Colorectal Diseases of Hubei Province (Zhongnan Hospital of Wuhan University), Wuhan, China,Hubei Key Laboratory of Intestinal and Colorectal Diseases (Zhongnan Hospital of Wuhan University), Wuhan, China,*Correspondence: Congqing Jiang, ; Xiaoyu Xie, ; Lifang Fan, ; Xianghai Ren,
| | - Congqing Jiang
- Department of Colorectal and Anal Surgery, Zhongnan Hospital of Wuhan University, Wuhan, China,Clinical Center of Intestinal and Colorectal Diseases of Hubei Province (Zhongnan Hospital of Wuhan University), Wuhan, China,Hubei Key Laboratory of Intestinal and Colorectal Diseases (Zhongnan Hospital of Wuhan University), Wuhan, China,*Correspondence: Congqing Jiang, ; Xiaoyu Xie, ; Lifang Fan, ; Xianghai Ren,
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17
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Yu I, Wu R, Tokumaru Y, Terracina KP, Takabe K. The Role of the Microbiome on the Pathogenesis and Treatment of Colorectal Cancer. Cancers (Basel) 2022; 14:5685. [PMID: 36428777 PMCID: PMC9688177 DOI: 10.3390/cancers14225685] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Revised: 11/13/2022] [Accepted: 11/16/2022] [Indexed: 11/22/2022] Open
Abstract
The gut microbiome has long been known to play a role in various aspects of health modulation, including the pathogenesis of colorectal cancer (CRC). With immunotherapy recently emerging as a successful treatment in microsatellite instability high (MSI-high) CRC, and with a newly demonstrated involvement of the gut microbiome in the modulation of therapeutic responses, there has been an explosion of research into the mechanisms of microbial effects on CRC. Harnessing and reprogramming the microbiome may allow for the expansion of these successes to broader categories of CRC, the prevention of CRC in high-risk patients, and the enhancement of standard treatments. In this review, we pull together both well-documented phenomena and recent discoveries that pertain to the microbiome and CRC. We explore the microbial mechanisms associated with CRC pathogenesis and progression, recent advancements in CRC systemic therapy, potential options for diagnosis and prevention, as well as directions for future research.
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Affiliation(s)
- Irene Yu
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA
- Department of Surgery, Jacobs School of Medicine and Biomedical Sciences, State University of New York, Buffalo, NY 14203, USA
| | - Rongrong Wu
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA
| | - Yoshihisa Tokumaru
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA
| | | | - Kazuaki Takabe
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA
- Department of Surgery, Jacobs School of Medicine and Biomedical Sciences, State University of New York, Buffalo, NY 14203, USA
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan
- Department of Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan
- Department of Breast Surgery and Oncology, Tokyo Medical University, Tokyo 160-8402, Japan
- Department of Breast Surgery, Fukushima Medical University, Fukushima 960-1295, Japan
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Feizi H, Plotnikov A, Rezaee MA, Ganbarov K, Kamounah FS, Nikitin S, Kadkhoda H, Gholizadeh P, Pagliano P, Kafil HS. Postbiotics versus probiotics in early-onset colorectal cancer. Crit Rev Food Sci Nutr 2022; 64:3573-3582. [PMID: 36250549 DOI: 10.1080/10408398.2022.2132464] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
Probiotics and postbiotics mechanisms of action and applications in early-onset colorectal cancer (EOCRC) prevention and treatment have significant importance but are a matter of debate and controversy. Therefore, in this review, we aimed to define the probiotics concept, advantages and limitations in comparison to postbiotics, and proposed mechanisms of anti-tumor action in EOCRC prevention and treatment of postbiotics. Biotics (probiotics, prebiotics, and postbiotics) could confer the health benefit by affecting the host gut microbiota directly and indirectly. The main mechanisms of action of probiotics in exerting anticancer features include immune system regulation, inhibition of cancer cell propagation, gut dysbiosis restoration, anticancer agents' production, gut barrier function renovation, and cancer-promoting agents' reduction. Postbiotics are suggested to have different mechanisms of action to restore eubiosis against EOCRC, including modulation of gut microbiota composition, gut microbial metabolites regulation, and intestinal barrier function improvement via different features such as immunomodulatory, anti-inflammatory, antioxidant, and anti-proliferative properties. A better understanding of postbiotics challenges and mechanism of action in therapeutic applications will allow us to sketch accurate trials in order to use postbiotics as bio-therapeutics in EOCRC.
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Affiliation(s)
- Hadi Feizi
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Andrey Plotnikov
- Institute for Cellular and Intracellular Symbiosis of the Ural Branch of the Russian Academy of Sciences, Orenburg, Russia
| | | | - Khudaverdi Ganbarov
- Research Laboratory of Microbiology and Virology, Baku State University, Baku, Azerbaijan
| | - Fadhil S Kamounah
- Department of Chemistry, University of Copenhagen, Copenhagen, Denmark
| | - Sergei Nikitin
- Department of Science and Environment, Roskilde University, Roskilde, Denmark
| | - Hiva Kadkhoda
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Pourya Gholizadeh
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Hossein Samadi Kafil
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
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Zhou X, Aikemu B, Li S, Shao Y, Jia H, Huang L, Hong H, Zhang S, Tang Q, Pan R, Sun J, Zheng M. Comprehensive exploration of tumor immune microenvironment feature and therapeutic response in colorectal cancer based on a novel immune-related long non-coding RNA prognostic signature. Front Genet 2022; 13:962575. [PMID: 36092924 PMCID: PMC9454821 DOI: 10.3389/fgene.2022.962575] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Accepted: 07/27/2022] [Indexed: 11/13/2022] Open
Abstract
Colorectal cancer (CRC) is one of the most common malignant tumors with a high incidence rate and mortality. LncRNA is an important regulator of the immune system. It is of great significance to study immune-related lncRNAs (IR-lncRNAs) for CRC. In this study, we screened IR-lncRNAs differentially expressed in normal and CRC tissues, and Univariate Cox regression and the Least Absolute Shrinkage and Selection Operator were applied to construct IR-lncRNA prognostic signature in TCGA training dataset, and its predictive capability for the prognosis of CRC patients was verified in GSE39582 validation dataset. The novel signature was identified as an independent predictor of prognosis in CRC patients. In addition, the signature could accurately predict the feature of the immune microenvironment and therapeutic response in CRC patients. The CMap database was adopted to screen for small molecule candidate drugs that can reverse and treat high-risk CRC patients. Finally, the expression of six IR-lncRNAs were verified by qRT-PCR in clinical specimens from our patient cohort. In conclusion, we construct an IR-lncRNA prognostic signature, which is a powerful biomarker of CRC and can accurately predict the prognosis, immune microenvironment feature, and therapeutic response of CRC patients.
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Affiliation(s)
- Xueliang Zhou
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Minimally Invasive Surgery Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Batuer Aikemu
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Minimally Invasive Surgery Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Shuchun Li
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Minimally Invasive Surgery Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yanfei Shao
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Minimally Invasive Surgery Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Hongtao Jia
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Minimally Invasive Surgery Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ling Huang
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Minimally Invasive Surgery Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Hiju Hong
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Minimally Invasive Surgery Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Sen Zhang
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Minimally Invasive Surgery Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Qiushi Tang
- Chinese Journal of Practical Surgery, China Medical University, Shenyang, China
- *Correspondence: Jing Sun, ; Ruijun Pan, ; Qiushi Tang,
| | - Ruijun Pan
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Minimally Invasive Surgery Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- *Correspondence: Jing Sun, ; Ruijun Pan, ; Qiushi Tang,
| | - Jing Sun
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Minimally Invasive Surgery Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- *Correspondence: Jing Sun, ; Ruijun Pan, ; Qiushi Tang,
| | - Minhua Zheng
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Minimally Invasive Surgery Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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20
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Xing C, Du Y, Duan T, Nim K, Chu J, Wang HY, Wang RF. Interaction between microbiota and immunity and its implication in colorectal cancer. Front Immunol 2022; 13:963819. [PMID: 35967333 PMCID: PMC9373904 DOI: 10.3389/fimmu.2022.963819] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Accepted: 07/08/2022] [Indexed: 11/13/2022] Open
Abstract
Colorectal cancer (CRC) is one of the leading causes of cancer-related death in the world. Besides genetic causes, colonic inflammation is one of the major risk factors for CRC development, which is synergistically regulated by multiple components, including innate and adaptive immune cells, cytokine signaling, and microbiota. The complex interaction between CRC and the gut microbiome has emerged as an important area of current CRC research. Metagenomic profiling has identified a number of prominent CRC-associated bacteria that are enriched in CRC patients, linking the microbiota composition to colitis and cancer development. Some microbiota species have been reported to promote colitis and CRC development in preclinical models, while a few others are identified as immune modulators to induce potent protective immunity against colitis and CRC. Mechanistically, microbiota regulates the activation of different immune cell populations, inflammation, and CRC via crosstalk between innate and adaptive immune signaling pathways, including nuclear factor kappa B (NF-κB), type I interferon, and inflammasome. In this review, we provide an overview of the potential interactions between gut microbiota and host immunity and how their crosstalk could synergistically regulate inflammation and CRC, thus highlighting the potential roles and mechanisms of gut microbiota in the development of microbiota-based therapies to prevent or alleviate colitis and CRC.
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Affiliation(s)
- Changsheng Xing
- Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Yang Du
- Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Tianhao Duan
- Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Kelly Nim
- Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Junjun Chu
- Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Helen Y. Wang
- Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Rong-Fu Wang
- Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
- Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
- Department of Pediatrics, Children’s Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
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21
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Ahmed T. Immunotherapy for neuroblastoma using mRNA vaccines. ADVANCES IN CANCER BIOLOGY - METASTASIS 2022; 4:100033. [DOI: 10.1016/j.adcanc.2022.100033] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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22
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CD40 monoclonal antibody and OK432 synergistically promote the activation of dendritic cells in immunotherapy. Cancer Cell Int 2022; 22:216. [PMID: 35715855 PMCID: PMC9206283 DOI: 10.1186/s12935-022-02630-x] [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: 11/30/2021] [Accepted: 06/08/2022] [Indexed: 12/05/2022] Open
Abstract
Background Colorectal cancer (CRC) with pulmonary metastasis usually indicates a poor prognosis, whereas patients may benefit from adoptive cell therapy. Tumor-specific cytotoxic T lymphocytes (CTLs) have been reported as a promising treatment for CRC. However, the antitumor effect of CTLs remains limited partially due to insufficient production of effector cells via the activation by antigen-presenting dendritic cells (DCs). Method This study showed that a combination of CD40 mAb and Picibanil (OK-432) could significantly enhance the activation of CTLs by DCs, both in vitro and in vivo. Flow cytometry, colon cancer mouse model, and pathological staining were employed to demonstrate the specific functions. Results This approach promoted the maturation of DCs, augmented the production of stimulatory cytokines, and suppressed the secretion of inhibitory cytokines. Additionally, it facilitated the killing efficiency of CTLs via stimulating their proliferation while restraining the number of Tregs, concomitantly with the positive regulation of corresponding cytokines. Furthermore, the combined unit could hurdle the expansion of tumor cells on metastatic lungs in the colon cancer mouse model. Conclusion Collectively, the combination of CD40-mAb and OK-432 facilitated the maturation of DCs and enhanced the cytotoxicity of T cells, promising therapeutic approach against CRC. Graphical Abstract ![]()
Supplementary Information The online version contains supplementary material available at 10.1186/s12935-022-02630-x.
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Zhang S, Wang Y, Zhang P, Ai L, Liu T. Cardiovascular Outcomes in the Patients With Colorectal Cancer: A Multi-Registry-Based Cohort Study of 197,699 Cases in the Real World. Front Cardiovasc Med 2022; 9:851833. [PMID: 35783821 PMCID: PMC9243221 DOI: 10.3389/fcvm.2022.851833] [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: 01/10/2022] [Accepted: 03/17/2022] [Indexed: 11/24/2022] Open
Abstract
PURPOSE We aimed to investigate the mortality patterns and quantitatively assess the risks of cardiovascular death (CVD) in patients with colorectal cancer (CRC). We also established a competing-risk model to predict the probability of CVD for patients with CRC. PATIENTS AND METHODS Patients with CRC who diagnosed between 2007 and 2015 in the Surveillance, Epidemiology, and End Results (SEER) database were included in the present study. The cumulative incidence function (CIF) was used for CVD and other causes of death, and Gray's test was used to determine the subgroup difference in CIF. The Fine-Gray proportional subdistribution hazards model was used for identifying independent risk factors for CVD. A novel competing-risk model was established to evaluate the probability of CVD for patients with CRC. The performance of the nomogram was measured by concordance index (C-index), calibration curve, decision curve analysis (DCA), and risk stratification. RESULTS After a median follow-up of 37.00 months, 79,455 deaths occurred, of whom 56,185 (70.71%) succumbed to CRC and 23,270 (29.29%) patients died due to non-CRC, among which CVD accounted for 9,702 (41.69%), being the major cause of non-cancer deaths. The 1-, 3-, and 5-year cumulative rates for CVD were 12.20, 24.25, and 30.51%, respectively. In multivariate analysis, age, race, marital status, tumor size, tumor stage, advanced stage, surgery, and chemotherapy were independent risk factors of CVD among patients with CRC. The nomogram was well calibrated and had good discriminative ability, with a c-index of 0.719 (95% CI, 0.738-0.742) in the training cohort and 0.719 (95% CI, 0.622-0.668) in the validation cohort. DCA demonstrated that nomogram produced more benefit within wide ranges of threshold probabilities for 1-, 3-, and 5-year CVD, respectively. CONCLUSION This study was the first to analyze the CIF and risk factors for CVD among CRC based on a competing-risk model. We have also built the first 1-, 3-, and 5-year competing nomogram for predicting CVD. This nomogram had excellent performance and could help clinicians to provide individualized management in clinical practice.
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Affiliation(s)
- Shilong Zhang
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yan Wang
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Pengfei Zhang
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Luoyan Ai
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Tianshu Liu
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai, China
- Centre for Evidence-Based Medicine, Fudan University, Shanghai, China
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24
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Feng Y, Chen Y, Chen Y, He X, Khan Y, Hu H, Lan P, Li Y, Wang X, Li G, Kaplan D. Intestinal stents: Structure, functionalization and advanced engineering innovation. BIOMATERIALS ADVANCES 2022; 137:212810. [PMID: 35929235 DOI: 10.1016/j.bioadv.2022.212810] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/08/2022] [Revised: 04/08/2022] [Accepted: 04/13/2022] [Indexed: 06/15/2023]
Abstract
Intestinal stents are a palliative treatment option that solves many shortcomings of traditional surgeries for cancer-induced intestinal obstructions. The present review provides an overview of the incidence, clinical manifestations and limitations in the treatment of intestinal cancers. The paper also discusses material property requirements, indications, complications and the future of stent-assisted therapy. The advantages and disadvantages of different materials and processing techniques for intestinal stents are reviewed along with new stent treatment combinations for colorectal cancer. Challenges that require further cooperative studies are also detailed. The future development of intestinal stents will depend on innovation in material designs as well as the utilization of multi-functional strategies and innovative engineering solutions.
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Affiliation(s)
- Yusheng Feng
- National Engineering Laboratory for Modern Silk, College of Textile and Clothing Engineering, Soochow University, Suzhou 215123, Jiangsu, China
| | - Yufeng Chen
- Department of Colorectal Surgery, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, Guangdong, China
| | - Ying Chen
- Department of Biomedical Engineering, Tufts University, 4 Colby Street, Medford, MA 02155, USA
| | - Xiaowen He
- Department of Colorectal Surgery, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, Guangdong, China
| | - Yousef Khan
- Department of Biomedical Engineering, Tufts University, 4 Colby Street, Medford, MA 02155, USA
| | - Hong Hu
- Institute of Textiles and Clothing, The Hong Kong Polytechnic University, Kowloon, Hong Kong, China
| | - Ping Lan
- Department of Colorectal Surgery, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, Guangdong, China
| | - Yi Li
- Department of Materials, University of Manchester, Oxford Road, Manchester M13 9PL, UK
| | - Xiaoqin Wang
- National Engineering Laboratory for Modern Silk, College of Textile and Clothing Engineering, Soochow University, Suzhou 215123, Jiangsu, China
| | - Gang Li
- National Engineering Laboratory for Modern Silk, College of Textile and Clothing Engineering, Soochow University, Suzhou 215123, Jiangsu, China.
| | - David Kaplan
- Department of Biomedical Engineering, Tufts University, 4 Colby Street, Medford, MA 02155, USA.
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25
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Gorzo A, Galos D, Volovat SR, Lungulescu CV, Burz C, Sur D. Landscape of Immunotherapy Options for Colorectal Cancer: Current Knowledge and Future Perspectives beyond Immune Checkpoint Blockade. Life (Basel) 2022; 12:229. [PMID: 35207516 PMCID: PMC8878674 DOI: 10.3390/life12020229] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Revised: 01/21/2022] [Accepted: 01/31/2022] [Indexed: 11/24/2022] Open
Abstract
Colorectal cancer is the third most prevalent malignancy in Western countries and a major cause of death despite recent improvements in screening programs and early detection methods. In the last decade, a growing effort has been put into better understanding how the immune system interacts with cancer cells. Even if treatments with immune checkpoint inhibitors (anti-PD1, anti-PD-L1, anti-CTLA4) were proven effective for several cancer types, the benefit for colorectal cancer patients is still limited. However, a subset of patients with deficient mismatch repair (dMMR)/microsatellite-instability-high (MSI-H) metastatic colorectal cancer has been observed to have a prolonged benefit to immune checkpoint inhibitors. As a result, pembrolizumab and nivolumab +/- ipilimumab recently obtained the Food and Drug Administration approval. This review aims to highlight the body of knowledge on immunotherapy in the colorectal cancer setting, discussing the potential mechanisms of resistance and future strategies to extend its use.
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Affiliation(s)
- Alecsandra Gorzo
- Department of Medical Oncology, The Oncology Institute “Prof. Dr. Ion Chiricuţă”, 400015 Cluj-Napoca, Romania; (A.G.); (D.G.); (C.B.)
- Department of Medical Oncology, University of Medicine and Pharmacy “Iuliu Hatieganu”, 400000 Cluj-Napoca, Romania
| | - Diana Galos
- Department of Medical Oncology, The Oncology Institute “Prof. Dr. Ion Chiricuţă”, 400015 Cluj-Napoca, Romania; (A.G.); (D.G.); (C.B.)
- Department of Medical Oncology, University of Medicine and Pharmacy “Iuliu Hatieganu”, 400000 Cluj-Napoca, Romania
| | - Simona Ruxandra Volovat
- Department of Medical Oncology, University of Medicine and Pharmacy “Grigore T. Popa” Iasi, 700115 Iasi, Romania;
| | | | - Claudia Burz
- Department of Medical Oncology, The Oncology Institute “Prof. Dr. Ion Chiricuţă”, 400015 Cluj-Napoca, Romania; (A.G.); (D.G.); (C.B.)
- Department of Allergology and Immunology, University of Medicine and Pharmacy “Iuliu Hatieganu”, 400000 Cluj-Napoca, Romania
| | - Daniel Sur
- Department of Medical Oncology, The Oncology Institute “Prof. Dr. Ion Chiricuţă”, 400015 Cluj-Napoca, Romania; (A.G.); (D.G.); (C.B.)
- Department of Medical Oncology, University of Medicine and Pharmacy “Iuliu Hatieganu”, 400000 Cluj-Napoca, Romania
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The Stroma Liquid Biopsy Panel Contains a Stromal-Epithelial Gene Signature Ratio That Is Associated with the Histologic Tumor-Stroma Ratio and Predicts Survival in Colon Cancer. Cancers (Basel) 2021; 14:cancers14010163. [PMID: 35008327 PMCID: PMC8750571 DOI: 10.3390/cancers14010163] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Revised: 12/18/2021] [Accepted: 12/27/2021] [Indexed: 12/22/2022] Open
Abstract
Liquid biopsy has emerged as a novel approach to tumor characterization, offering advantages in sample accessibility and tissue heterogeneity. However, as mutational analysis predominates, the tumor microenvironment has largely remained unacknowledged in liquid biopsy research. The current work provides an explorative transcriptomic characterization of the Stroma Liquid BiopsyTM (SLB) proteomics panel in colon carcinoma by integrating single-cell and bulk transcriptomics data from publicly available repositories. Expression of SLB genes was significantly enriched in tumors with high histologic stromal content in comparison to tumors with low stromal content (median enrichment score 0.308 vs. 0.222, p = 0.036). In addition, we identified stromal-specific and epithelial-specific expression of the SLB genes, that was subsequently integrated into a gene signature ratio. The stromal-epithelial signature ratio was found to have prognostic significance in a discovery cohort of 359 colon adenocarcinoma patients (OS HR 2.581, 95%CI 1.567-4.251, p < 0.001) and a validation cohort of 229 patients (OS HR 2.590, 95%CI 1.659-4.043, p < 0.001). The framework described here provides transcriptomic evidence for the prognostic significance of the SLB panel constituents in colon carcinoma. Plasma protein levels of the SLB panel may reflect histologic intratumoral stromal content, a poor prognostic tumor characteristic, and hence provide valuable prognostic information in liquid biopsy.
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