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1
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Zou D, Xin X, Xu H, Xu Y, Xu T. Development and validation of a cancer-associated fibroblast gene signature-based model for predicting immunotherapy response in colon cancer. Sci Rep 2025; 15:16550. [PMID: 40360558 PMCID: PMC12075585 DOI: 10.1038/s41598-025-01185-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2024] [Accepted: 05/05/2025] [Indexed: 05/15/2025] Open
Abstract
The efficacy of immune checkpoint inhibitors in colon cancer has been established, and there is an urgent need to identify new molecular markers for colon cancer immunotherapy to guide clinical decisions. Using the "EPIC" and "MCPcounter" R packages to conduct cancer-associated fibroblast (CAF) infiltration scoring on colon cancer samples from the TCGA database and the GEO database, the WGCNA analysis was performed on the two databases' samples based on the CAF infiltration scores to screen for CAF-related genes. LASSO regression analysis was used to construct a risk model with these genes. Comprehensive bioinformatics analysis was conducted on the constructed model to evaluate the stability of its prediction of CAF infiltration abundance and the stability of its prediction of immunotherapy efficacy. The newly constructed risk model could well reflect the abundance of CAF infiltration in colon cancer, with a correlation coefficient of 0.91 in the training cohort TCGA-COAD and 0.88 in the validation cohort GSE39582. GSEA analysis revealed that CAF is closely related to functions associated with extracellular matrix remodeling. The constructed risk model can predict the efficacy of immunotherapy in colon cancer well, with the high-risk group showing significantly poorer immunotherapy response than the low-risk group, with an expected effective rate of immunotherapy of 68 vs. 24% in the training group (P < 0.001) and 64 vs. 26% in the validation group (P < 0.001). The AUC value for predicting immunotherapy response by the risk model in the training group was 0.780 (95% CI 0.736-0.820), and in the validation group, the AUC value was 0.774 (95% CI 0.735-0.810). Drug sensitivity analysis showed that the expected chemotherapeutic effect in the low-risk group was superior to that in the high-risk group. CAF is associated with immunosuppression and drug resistance. Predicting the efficacy of immunotherapy in colon cancer based on the abundance of CAF infiltration is a feasible approach. For the high-risk population identified by our model, clinical consideration should be given to prioritizing non-immunotherapy approaches to avoid potential risks associated with immunotherapy.
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Affiliation(s)
- Daoyang Zou
- The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China
| | - Xi Xin
- Ganzhou People's Hospital, Ganzhou, China
| | - Huangzhen Xu
- The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China
| | - Yunxian Xu
- The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China
| | - Tianwen Xu
- The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China.
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2
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Awosika JA, Gulley JL, Pastor DM. Deficient Mismatch Repair and Microsatellite Instability in Solid Tumors. Int J Mol Sci 2025; 26:4394. [PMID: 40362635 PMCID: PMC12072705 DOI: 10.3390/ijms26094394] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2025] [Revised: 04/26/2025] [Accepted: 04/27/2025] [Indexed: 05/15/2025] Open
Abstract
The integrity of the genome is maintained by mismatch repair (MMR) proteins that recognize and repair base mismatches and insertion/deletion errors generated during DNA replication and recombination. A defective MMR system results in genome-wide instability and the progressive accumulation of mutations. Tumors exhibiting deficient MMR (dMMR) and/or high levels of microsatellite instability (termed "microsatellite instability high", or MSI-H) have been shown to possess fundamental differences in clinical, pathological, and molecular characteristics, distinguishing them from their "microsatellite stable" (MSS) counterparts. Molecularly, they are defined by a high mutational burden, genetic instability, and a distinctive immune profile. Their distinct genetic and immunological profiles have made dMMR/MSI-H tumors particularly amenable to treatment with immune checkpoint inhibitors (ICIs). The ongoing development of biomarker-driven therapies and the evaluation of novel combinations of immune-based therapies, with or without the use of conventional cytotoxic treatment regimens, continue to refine treatment strategies with the goals of maximizing therapeutic efficacy and survival outcomes in this distinct patient population. Moreover, the resultant knowledge of the mechanisms by which these features are suspected to render these tumors more responsive, overall, to immunotherapy may provide information regarding the potential optimization of this therapeutic approach in tumors with proficient MMR (pMMR)/MSS tumors.
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Affiliation(s)
- Joy A. Awosika
- Gastrointestinal Malignancies Section, Thoracic & GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - James L. Gulley
- Center for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Danielle M. Pastor
- Center for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
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3
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Huffman BM, Rahma OE, Tyan K, Li YY, Giobbie-Hurder A, Schlechter BL, Bockorny B, Manos MP, Cherniack AD, Baginska J, Mariño-Enríquez A, Kao KZ, Maloney AK, Ferro A, Kelland S, Ng K, Singh H, Welsh EL, Pfaff KL, Giannakis M, Rodig SJ, Hodi FS, Cleary JM. A Phase I Trial of Trebananib, an Angiopoietin 1 and 2 Neutralizing Peptibody, Combined with Pembrolizumab in Patients with Advanced Ovarian and Colorectal Cancer. Cancer Immunol Res 2025; 13:9-22. [PMID: 39348472 DOI: 10.1158/2326-6066.cir-23-1027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2023] [Revised: 04/08/2024] [Accepted: 09/25/2024] [Indexed: 10/02/2024]
Abstract
Ovarian cancers and microsatellite stable (MSS) colorectal cancers are insensitive to anti-programmed cell death 1 (PD-1) immunotherapy, and new immunotherapeutic approaches are needed. Preclinical data suggest a relationship between immunotherapy resistance and elevated angiopoietin 2 levels. We performed a phase I dose escalation study of pembrolizumab and the angiopoietin 1/2 inhibitor trebananib (NCT03239145). This multicenter trial enrolled patients with metastatic ovarian cancer or MSS colorectal cancer. Trebananib was administered intravenously weekly for 12 weeks with 200 mg intravenous pembrolizumab every 3 weeks. The toxicity profile of this combination was manageable, and the protocol-defined highest dose level (trebananib 30 mg/kg weekly plus pembrolizumab 200 mg every 3 weeks) was declared the maximum tolerated dose. The objective response rate for all patients was 7.3% (90% confidence interval, 2.5%-15.9%). Three patients with MSS colorectal cancer had durable responses for ≥3 years. One responding patient's colorectal cancer harbored a POLE mutation. The other two responding patients had left-sided colorectal cancers, with no baseline liver metastases, and genomic analysis revealed that they both had KRAS wild-type, ERBB2-amplified tumors. After development of acquired resistance, biopsy of one patient's KRAS wild-type ERBB2-amplified tumor showed a substantial decline in tumor-associated T cells and an increase in immunosuppressive intratumoral macrophages. Future studies are needed to carefully assess whether clinicogenomic features, such as lack of liver metastases, ERBB2 amplification, and left-sided tumors, can predict increased sensitivity to PD-1 immunotherapy combinations.
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Affiliation(s)
- Brandon M Huffman
- Harvard Medical School, Boston, Massachusetts
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Osama E Rahma
- Harvard Medical School, Boston, Massachusetts
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Kevin Tyan
- Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts
| | - Yvonne Y Li
- Harvard Medical School, Boston, Massachusetts
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Anita Giobbie-Hurder
- Division of Biostatistics, Department of Data Sciences, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Benjamin L Schlechter
- Harvard Medical School, Boston, Massachusetts
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Bruno Bockorny
- Harvard Medical School, Boston, Massachusetts
- Department of Medical Oncology, Beth Israel Deaconess Medical Center, Boston, Massachusetts
| | - Michael P Manos
- Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts
- Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Andrew D Cherniack
- Harvard Medical School, Boston, Massachusetts
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
- The Broad Institute of Harvard and MIT, Cambridge, Massachusetts
| | - Joanna Baginska
- Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts
- Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Adrián Mariño-Enríquez
- Harvard Medical School, Boston, Massachusetts
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Katrina Z Kao
- Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts
- Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Anna K Maloney
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Allison Ferro
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Sarah Kelland
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Kimmie Ng
- Harvard Medical School, Boston, Massachusetts
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Harshabad Singh
- Harvard Medical School, Boston, Massachusetts
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Emma L Welsh
- Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts
- Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Kathleen L Pfaff
- Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts
- Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Marios Giannakis
- Harvard Medical School, Boston, Massachusetts
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
- The Broad Institute of Harvard and MIT, Cambridge, Massachusetts
| | - Scott J Rodig
- Harvard Medical School, Boston, Massachusetts
- Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts
- Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
- ImmunoProfile, Brigham and Women's Hospital and Dana-Farber Cancer Institute, Boston, Massachusetts
| | - F Stephen Hodi
- Harvard Medical School, Boston, Massachusetts
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - James M Cleary
- Harvard Medical School, Boston, Massachusetts
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
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4
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Ferkel SAM, Holman EA, Sojwal RS, Rubin SJS, Rogalla S. Tumor-Infiltrating Immune Cells in Colorectal Cancer. Neoplasia 2025; 59:101091. [PMID: 39642846 DOI: 10.1016/j.neo.2024.101091] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2024] [Accepted: 11/18/2024] [Indexed: 12/09/2024]
Abstract
Colorectal cancer encompasses a heterogeneous group of malignancies that differ in pathophysiological mechanisms, immune response and infiltration, therapeutic response, and clinical prognosis. Numerous studies have highlighted the clinical relevance of tumor-infiltrating immune cells among different types of colorectal tumors yet vary in cell type definitions and cell identification strategies. The distinction of immune signatures is particularly challenging when several immune subtypes are involved but crucial to identify novel intercellular mechanisms within the tumor microenvironment. In this review, we compile human and non-human studies on tumor-infiltrating immune cells and provide an overview of immune subtypes, their pathophysiological functions, and their prognostic role in colorectal cancer. We discuss how differentiating immune signatures can guide the development of immunotherapeutic targets and personalized treatment regimens. We analyzed comprehensive human protein biomarker profiles across the entire immune spectrum to improve interpretability and application of tumor studies and to ultimately enhance immunotherapy and advance precision medicine for colorectal cancer patients.
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Affiliation(s)
- Sonia A M Ferkel
- Stanford University, School of Medicine, Department of Medicine, Division of Gastroenterology and Hepatology, Stanford, USA
| | - Elizabeth A Holman
- Stanford University, School of Medicine, Department of Medicine, Division of Gastroenterology and Hepatology, Stanford, USA
| | - Raoul S Sojwal
- Stanford University, School of Medicine, Department of Medicine, Division of Gastroenterology and Hepatology, Stanford, USA
| | - Samuel J S Rubin
- Stanford University, School of Medicine, Department of Medicine, Division of Gastroenterology and Hepatology, Stanford, USA
| | - Stephan Rogalla
- Stanford University, School of Medicine, Department of Medicine, Division of Gastroenterology and Hepatology, Stanford, USA.
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5
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Qu F, Wu S, Yu W. Progress of Immune Checkpoint Inhibitors Therapy for pMMR/MSS Metastatic Colorectal Cancer. Onco Targets Ther 2024; 17:1223-1253. [PMID: 39735789 PMCID: PMC11681808 DOI: 10.2147/ott.s500281] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2024] [Accepted: 12/12/2024] [Indexed: 12/31/2024] Open
Abstract
Immunotherapy is one of the research hotspots in colorectal cancer field in recent years. The colorectal cancer patients with mismatch repair-deficient (dMMR) or high microsatellite instability (MSI-H) are the primary beneficiaries of immunotherapy. However, the vast majority of colorectal cancers are mismatch repair proficient (pMMR) or microsatellite stability (MSS), and their immune microenvironment is characterized by "cold tumors" that are generally insensitive to single immunotherapy based on immune checkpoint inhibitors (ICIs). Studies have shown that some pMMR/MSS colorectal cancer patients regulate the immune microenvironment by combining other treatments, such as multi-target tyrosine kinase inhibitors, anti-vascular endothelial growth factor (VEGF) monoclonal antibodies, chemotherapy, radiotherapy, anti-epithelial growth factor receptor (EGFR) monoclonal antibodies, and mitogen-activated protein kinase (MAPK) signaling pathway inhibitors and oncolytic viruses, etc. to transform "cold tumor" into "hot tumor", thereby improving the response to immunotherapy. In addition, screening for potential prognostic biomarkers can also enrich the population benefiting from immunotherapy for microsatellite stable colorectal cancer. Therefore, in pMMR or MSS metastatic colorectal cancer (mCRC), the optimization of immunotherapy regimens and the search for effective efficacy prediction biomarkers are currently important research directions. In this paper, we review the progress of efficacy of immunotherapy (mainly ICIs) in pMMR /MSS mCRC, challenges and potential markers, in order to provide research ideas for the development of immunotherapy for mCRC.
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Affiliation(s)
- Fanjie Qu
- Department of Oncology, Affiliated Dalian Third People’s Hospital of Dalian Medical University, Dalian, Liaoning Province, 116033, People’s Republic of China
| | - Shuang Wu
- Department of Oncology, Affiliated Dalian Third People’s Hospital of Dalian Medical University, Dalian, Liaoning Province, 116033, People’s Republic of China
| | - WeiWei Yu
- Department of Oncology, Affiliated Dalian Third People’s Hospital of Dalian Medical University, Dalian, Liaoning Province, 116033, People’s Republic of China
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6
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Li P, Huang D. Targeting the JAK-STAT pathway in colorectal cancer: mechanisms, clinical implications, and therapeutic potential. Front Cell Dev Biol 2024; 12:1507621. [PMID: 39659524 PMCID: PMC11628519 DOI: 10.3389/fcell.2024.1507621] [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: 10/08/2024] [Accepted: 11/11/2024] [Indexed: 12/12/2024] Open
Abstract
Colorectal cancer (CRC) remains one of the most prevalent and fatal malignancies worldwide, consistently ranking among the top three in terms of incidence and mortality. Despite notable advancements in early detection and therapeutic interventions, survival outcomes for advanced-stage CRC are still dismal, largely due to issues such as drug resistance and metastasis. Recent research has increasingly implicated the JAK-STAT signaling pathway as a pivotal contributor to CRC pathogenesis. This evolutionarily conserved pathway plays a key role in transmitting extracellular signals to the nucleus, thereby modulating gene expression involved in numerous fundamental biological processes. In CRC, dysregulation of the JAK-STAT pathway is frequently observed and is strongly associated with tumor progression, including processes such as cellular proliferation, apoptosis, metastasis, immune evasion, and the sustenance of cancer stem cells. Given its integral role in CRC advancement, the JAK-STAT pathway has gained recognition as a viable therapeutic target. Extensive evidence from preclinical and clinical models supports the efficacy and safety of targeting components of the JAK-STAT pathway, presenting new therapeutic possibilities for patients with CRC, particularly in addressing drug resistance and enhancing treatment outcomes. This review offers a detailed exploration of the JAK-STAT pathway, focusing on its regulatory mechanisms in CRC-related malignancies. Moreover, it examines the association between JAK-STAT protein expression, clinical features, prognosis, and its therapeutic potential in CRC management.
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Affiliation(s)
- Penghui Li
- Department of Gastrointestinal Surgery, The First Affiliated Hospital, College of Clinical Medicine, Henan University of Science and Technology, Luoyang, Henan, China
| | - Di Huang
- Department of Child Health Care, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
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7
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Chong X, Madeti Y, Cai J, Li W, Cong L, Lu J, Mo L, Liu H, He S, Yu C, Zhou Z, Wang B, Cao Y, Wang Z, Shen L, Wang Y, Zhang X. Recent developments in immunotherapy for gastrointestinal tract cancers. J Hematol Oncol 2024; 17:65. [PMID: 39123202 PMCID: PMC11316403 DOI: 10.1186/s13045-024-01578-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2024] [Accepted: 07/18/2024] [Indexed: 08/12/2024] Open
Abstract
The past few decades have witnessed the rise of immunotherapy for Gastrointestinal (GI) tract cancers. The role of immune checkpoint inhibitors (ICIs), particularly programmed death protein 1 (PD-1) and PD ligand-1 antibodies, has become increasingly pivotal in the treatment of advanced and perioperative GI tract cancers. Currently, anti-PD-1 plus chemotherapy is considered as first-line regimen for unselected advanced gastric/gastroesophageal junction adenocarcinoma (G/GEJC), mismatch repair deficient (dMMR)/microsatellite instability-high (MSI-H) colorectal cancer (CRC), and advanced esophageal cancer (EC). In addition, the encouraging performance of claudin18.2-redirected chimeric antigen receptor T-cell (CAR-T) therapy in later-line GI tract cancers brings new hope for cell therapy in solid tumour treatment. Nevertheless, immunotherapy for GI tumour remains yet precise, and researchers are dedicated to further maximising and optimising the efficacy. This review summarises the important research, latest progress, and future directions of immunotherapy for GI tract cancers including EC, G/GEJC, and CRC.
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Affiliation(s)
- Xiaoyi Chong
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, 52 Fucheng Road, Hai-Dian District, Beijing, 100142, China
| | - Yelizhati Madeti
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, 52 Fucheng Road, Hai-Dian District, Beijing, 100142, China
| | - Jieyuan Cai
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, 52 Fucheng Road, Hai-Dian District, Beijing, 100142, China
| | - Wenfei Li
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, 52 Fucheng Road, Hai-Dian District, Beijing, 100142, China
| | - Lin Cong
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, 52 Fucheng Road, Hai-Dian District, Beijing, 100142, China
| | - Jialin Lu
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, 52 Fucheng Road, Hai-Dian District, Beijing, 100142, China
| | - Liyang Mo
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, 52 Fucheng Road, Hai-Dian District, Beijing, 100142, China
| | - Huizhen Liu
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, 52 Fucheng Road, Hai-Dian District, Beijing, 100142, China
| | - Siyi He
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, 52 Fucheng Road, Hai-Dian District, Beijing, 100142, China
| | - Chao Yu
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, 52 Fucheng Road, Hai-Dian District, Beijing, 100142, China
| | - Zhiruo Zhou
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, 52 Fucheng Road, Hai-Dian District, Beijing, 100142, China
| | - Boya Wang
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, 52 Fucheng Road, Hai-Dian District, Beijing, 100142, China
| | - Yanshuo Cao
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, 52 Fucheng Road, Hai-Dian District, Beijing, 100142, China
| | - Zhenghang Wang
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, 52 Fucheng Road, Hai-Dian District, Beijing, 100142, China
| | - Lin Shen
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, 52 Fucheng Road, Hai-Dian District, Beijing, 100142, China
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Carcinogenesis and Translational Research, Department of Gastrointestinal Oncology, Peking University Cancer Hospital and Institute, Beijing, 100142, China
| | - Yakun Wang
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, 52 Fucheng Road, Hai-Dian District, Beijing, 100142, China.
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Carcinogenesis and Translational Research, Department of Gastrointestinal Oncology, Peking University Cancer Hospital and Institute, Beijing, 100142, China.
| | - Xiaotian Zhang
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, 52 Fucheng Road, Hai-Dian District, Beijing, 100142, China.
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Carcinogenesis and Translational Research, Department of Gastrointestinal Oncology, Peking University Cancer Hospital and Institute, Beijing, 100142, China.
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8
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Yang C, Zhao L, Lin Y, Wang S, Ye Y, Shen Z. Improving the efficiency of immune checkpoint inhibitors for metastatic pMMR/MSS colorectal cancer: Options and strategies. Crit Rev Oncol Hematol 2024; 200:104204. [PMID: 37984588 DOI: 10.1016/j.critrevonc.2023.104204] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2023] [Revised: 10/24/2023] [Accepted: 11/13/2023] [Indexed: 11/22/2023] Open
Abstract
Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment and been extensively used for patients with metastastic colorectal cancer (mCRC), especially those harboring deficient mismatch repair/ microsatellite instability (dMMR/MSI). However, the majority of mCRC are classified as proficient mismatch repair/microsatellite stability(pMMR/MSS) type characterized by a cold immune microenvironment, rendering them generally unresponsive to ICIs. How to improve the efficacy of ICIs for these patients is an important issue to be solved. On the one hand, it is urgent to discover the predictive biomarkers and clinical characteristics associated with effectiveness and expand the subset of pMMR/MSS mCRC patients who benefit from ICIs. Additionally, combined strategies are being explored to modulate the immune microenvironment of pMMR/MSS CRC and facilitate the conversion of cold tumors into hot tumors. In this review, we have focused on the recent advancements in the predictive biomarkers and combination therapeutic strategies with ICIs for pMMR/MSS mCRC.
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Affiliation(s)
- Changjiang Yang
- Department of Gastroenterological Surgery, Laboratory of Surgical Oncology, Beijing Key Laboratory of Colorectal Cancer Diagnosis and Treatment Research, Peking University People's Hospital, No.11 Xizhimen South Street, Beijing 100044, PR China
| | - Long Zhao
- Department of Gastroenterological Surgery, Laboratory of Surgical Oncology, Beijing Key Laboratory of Colorectal Cancer Diagnosis and Treatment Research, Peking University People's Hospital, No.11 Xizhimen South Street, Beijing 100044, PR China
| | - Yilin Lin
- Department of Gastroenterological Surgery, Laboratory of Surgical Oncology, Beijing Key Laboratory of Colorectal Cancer Diagnosis and Treatment Research, Peking University People's Hospital, No.11 Xizhimen South Street, Beijing 100044, PR China
| | - Shan Wang
- Department of Gastroenterological Surgery, Laboratory of Surgical Oncology, Beijing Key Laboratory of Colorectal Cancer Diagnosis and Treatment Research, Peking University People's Hospital, No.11 Xizhimen South Street, Beijing 100044, PR China
| | - Yingjiang Ye
- Department of Gastroenterological Surgery, Laboratory of Surgical Oncology, Beijing Key Laboratory of Colorectal Cancer Diagnosis and Treatment Research, Peking University People's Hospital, No.11 Xizhimen South Street, Beijing 100044, PR China
| | - Zhanlong Shen
- Department of Gastroenterological Surgery, Laboratory of Surgical Oncology, Beijing Key Laboratory of Colorectal Cancer Diagnosis and Treatment Research, Peking University People's Hospital, No.11 Xizhimen South Street, Beijing 100044, PR China.
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9
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Mencel J, Alves A, Angelis V, Gerlinger M, Starling N. State of the art: Targeting microsatellite instability in gastrointestinal cancers. Crit Rev Oncol Hematol 2024; 199:104387. [PMID: 38734279 DOI: 10.1016/j.critrevonc.2024.104387] [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: 01/18/2024] [Revised: 05/01/2024] [Accepted: 05/06/2024] [Indexed: 05/13/2024] Open
Abstract
DNA mismatch repair (MMR) deficiency and the associated microsatellite instability (MSI) phenotype has become a subject of enormous interest in recent years due to the demonstrated efficacy of immune checkpoint inhibitors (ICI) in advanced tumours. Assessing MSI in patients with gastrointestinal tract (GI) cancers is useful to exclude Lynch syndrome, but also to predict benefit for ICI. Following review of the relevant literature, this review article aims to outline the clinicopathologic spectrum of MSI and mismatch repair deficiency (dMMR) in the GI tract, hepatobiliary system and pancreas and discuss the therapeutic consideration in this disease.
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Affiliation(s)
- Justin Mencel
- Gastrointestinal and Lymphoma Unit, Royal Marsden NHS Foundation, London, United Kingdom
| | - Anneke Alves
- Gastrointestinal and Lymphoma Unit, Royal Marsden NHS Foundation, London, United Kingdom
| | - Vasileios Angelis
- Gastrointestinal and Lymphoma Unit, Royal Marsden NHS Foundation, London, United Kingdom
| | - Marco Gerlinger
- Gastrointestinal and Lymphoma Unit, Royal Marsden NHS Foundation, London, United Kingdom
| | - Naureen Starling
- Gastrointestinal and Lymphoma Unit, Royal Marsden NHS Foundation, London, United Kingdom.
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10
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Wang Y, Gao L, Ma B, Shi J, Yin Z, Zhu W, Chen H. Accelerated clinical response achieved by combining short-term tumor-directed photodynamic therapy with immunotherapy-based systemic therapies in synchronous colorectal cancer with MSI-H and POLE mutation: a case report. Front Immunol 2024; 15:1402334. [PMID: 39007151 PMCID: PMC11239333 DOI: 10.3389/fimmu.2024.1402334] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2024] [Accepted: 06/14/2024] [Indexed: 07/16/2024] Open
Abstract
Genetic sequencing has revolutionized immunotherapy in colorectal cancer (CRC). Recent clinical trials have revealed a positive response to immunotherapy-based systemic therapies in CRC patient subgroups with microsatellite instability (MSI)-High or DNA polymerase epsilon (POLE) mutation. However, the unsatisfactory response rates was the major limitation in real-world practice of the precision immunotherapy in CRC. Adding photodynamic therapy (PDT) to systemic immunotherapy has showed synergetic anti-tumor effect by modulating tumor microenvironment, while the eligible patient's subgroups which would benefit from this combination remained equivocal. Here we reported a synchronous colorectal cancer patient with MSI-High and POLE mutation who had accelerated response in less than 2 cycles (42 days) of immunotherapy-based systemic therapies after tumor-directed PDT and has remained progression-free by far. This case enlightened the synergetic effect of PDT in immunotherapy-treated CRC patients, with the MSI and POLE-mutation status as predictors of survival benefits.
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Affiliation(s)
- Yuhan Wang
- Lanzhou University Second Hospital, Lanzhou, China
| | - Lei Gao
- Lanzhou University Second Hospital, Lanzhou, China
| | - Bin Ma
- Lanzhou University Second Hospital, Lanzhou, China
| | - Jianming Shi
- Lanzhou University Second Hospital, Lanzhou, China
| | - Zhenyu Yin
- Lanzhou University Second Hospital, Lanzhou, China
| | - Weidong Zhu
- Department of General Surgery, Lintao County People’s Hospital in Gansu Province, Lintao, China
| | - Hao Chen
- Department of Surgical Oncology, Gansu Provincial Key Laboratory Of Environmental Oncology, Lanzhou University Second Hospital, Lanzhou, China
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11
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Lei JJ, Rao J, Feng HY, Cao DD, Yan HL, Yuan JP, Jiang ZM, Zhang YQ. Case report: Innovative treatment for one metastatic thyroid-like follicular carcinoma of the kidney with ATM and POLE mutations. Front Oncol 2024; 14:1352865. [PMID: 38933440 PMCID: PMC11199531 DOI: 10.3389/fonc.2024.1352865] [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: 12/09/2023] [Accepted: 05/10/2024] [Indexed: 06/28/2024] Open
Abstract
Thyroid-like follicular renal cell carcinoma (TLFRCC), also known as thyroid-like follicular carcinoma of the kidney or thyroid follicular carcinoma like renal tumor, is an exceedingly rare variant of renal cell carcinoma that has only recently been acknowledged. This neoplasm exhibits a distinct follicular morphology resembling that of the thyroid gland. Immunohistochemical analysis reveals positive expression of PAX8, Vimentin, and EMA, while thyroid-specific markers TG and TTF1 are consistently absent. Furthermore, there is a notable absence of any concurrent thyroid pathology on clinical evaluation. Previous reports have suggested that TLFRCC is an indolent, slow-growing malignancy with infrequent metastatic potential. In this report, we present a case of TLFRCC characterized by remarkable ossification and widespread metastasis, including multifocal pulmonary lesions, involvement of the abdominal wall, and infiltration into the psoas muscle. To our knowledge, this represents only the third documented instance of distant metastasis in thyroid follicular renal carcinoma. The current case demonstrates a therapeutic approach that combines radiotherapy with the utilization of toripalimab, a programmed cell death 1 (PD-1) receptor inhibitor, and pazopanib. This treatment regimen was tailored based on comprehensive genomic profiling, which identified mutations in the POLE (catalytic subunit of DNA polymerase epsilon) and ATM (ataxia-telangiectasia mutated) genes, both of which have been implicated in the pathogenesis of various malignant tumors. These findings represent a novel discovery, as such mutations have never been reported in association with TLFRCC. Thus far, this therapeutic approach has proven to be the most efficacious option for treating metastatic TLFRCC among previously reported, and it also marks the first mention of the potential benefits of radiotherapy in managing this particular subtype of renal cell carcinoma.
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Affiliation(s)
- Jin-Ju Lei
- Cancer Center, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Jie Rao
- Department of Pathology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Hong-Yan Feng
- Department of PET/CT Center, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - De-Dong Cao
- Cancer Center, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Hong-Lin Yan
- Department of Pathology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Jing-Ping Yuan
- Department of Pathology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Zhen-Min Jiang
- Cancer Center, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Yi-Qiao Zhang
- Cancer Center, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
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12
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Yan S, Wang W, Feng Z, Xue J, Liang W, Wu X, Tan Z, Zhang X, Zhang S, Li X, Zhang C. Immune checkpoint inhibitors in colorectal cancer: limitation and challenges. Front Immunol 2024; 15:1403533. [PMID: 38919624 PMCID: PMC11196401 DOI: 10.3389/fimmu.2024.1403533] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2024] [Accepted: 05/23/2024] [Indexed: 06/27/2024] Open
Abstract
Colorectal cancer exhibits a notable prevalence and propensity for metastasis, but the current therapeutic interventions for metastatic colorectal cancer have yielded suboptimal results. ICIs can decrease tumor development by preventing the tumor's immune evasion, presenting cancer patients with a new treatment alternative. The increased use of immune checkpoint inhibitors (ICIs) in CRC has brought several issues. In particular, ICIs have demonstrated significant clinical effectiveness in patients with MSI-H CRC, whereas their efficacy is limited in MSS. Acquired resistance can still occur in patients with a positive response to ICIs. This paper describes the efficacy of ICIs currently in the clinical treatment of CRC, discusses the mechanisms by which acquired resistance occurs, primarily related to loss and impaired presentation of tumor antigens, reduced response of IFN-λ and cytokine or metabolic dysregulation, and summarizes the incidence of adverse effects. We posit that the future of ICIs hinges upon the advancement of precise prediction biomarkers and the implementation of combination therapies. This study aims to elucidate the constraints associated with ICIs in CRC and foster targeted problem-solving approaches, thereby enhancing the potential benefits for more patients.
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Affiliation(s)
- Suying Yan
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Wanting Wang
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Zhiqiang Feng
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Jun Xue
- Department of General Surgery, The First Affiliated Hospital of Hebei North University, Zhangjiakou, China
| | - Weizheng Liang
- Central Laboratory, The First Affiliated Hospital of Hebei North University, Zhangjiakou, China
| | - Xueliang Wu
- Department of General Surgery, The First Affiliated Hospital of Hebei North University, Zhangjiakou, China
- Institute of Cancer, The First Affiliated Hospital of Hebei North University, Zhangjiakou, China
| | - Zhiquan Tan
- Department of Scientific and Technical Information, Tianjin Union Medical Center, Tianjin, China
| | - Xipeng Zhang
- Department of Colorectal Surgery, Tianjin Union Medical Center, Tianjin, China
- The Institute of Translational Medicine, Tianjin Union Medical Center of Nankai University, Tianjin, China
- Tianjin Institute of Coloproctology, Tianjin, China
| | - Shuai Zhang
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Xichuan Li
- Tianjin Key Laboratory of Animal and Plant Resistance, College of Life Sciences, Tianjin Normal University, Tianjin, China
| | - Chunze Zhang
- Department of Colorectal Surgery, Tianjin Union Medical Center, Tianjin, China
- The Institute of Translational Medicine, Tianjin Union Medical Center of Nankai University, Tianjin, China
- Tianjin Institute of Coloproctology, Tianjin, China
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13
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Devalle S, Aran V, Bastos Júnior CDS, Pannain VL, Brackmann P, Gregório ML, Ferreira Manso JE, Moura Neto V. A panorama of colon cancer in the era of liquid biopsy. THE JOURNAL OF LIQUID BIOPSY 2024; 4:100148. [PMID: 40027146 PMCID: PMC11863817 DOI: 10.1016/j.jlb.2024.100148] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/19/2024] [Revised: 03/13/2024] [Accepted: 03/13/2024] [Indexed: 03/05/2025]
Abstract
Colon cancer (CC) is one of the most frequent cancers worldwide being responsible for over 500 thousand deaths in 2022. Its financial and human burden is expected to increase in the next decades accompanying the growing and aging of the global population. Much of this burden could be alleviated considering that the lethality of CC is mostly due to its late diagnosis and failure in the individualized management of patients. Coordinated government actions and implementation of better diagnostic tools capable of detecting CC earlier and of tracking tumoral evolution are mandatory to achieve a reduction in CC's social impact. CtDNA-based liquid biopsy (LB) has great potential to contribute to patients' screening adhesion, CC earlier detection, and to longitudinal tumor follow-up. In this review, we will discuss the latest epidemiological data on CC disease, diagnostic, subtypes, genetics, and treatment management focusing on the advantages and limitations of ctDNA-based LB, including important bottlenecks and solutions necessary for its clinical translation. The latest ctDNA-directed CC clinical trials will also be examined.
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Affiliation(s)
- Sylvie Devalle
- Instituto Estadual do Cérebro Paulo Niemeyer, Secretaria de Estado de Saúde, Rio de Janeiro, Brazil
| | - Veronica Aran
- Instituto Estadual do Cérebro Paulo Niemeyer, Secretaria de Estado de Saúde, Rio de Janeiro, Brazil
| | | | - Vera Lucia Pannain
- Departamento de Patologia, Faculdade de Medicina, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Paulo Brackmann
- Clínica de Coloproctologia do Hospital Naval Marcílio Dias - IPB/HNMD, Rio de Janeiro, Brazil
| | - Marcelo Leal Gregório
- Instituto de Pesquisas Biomédicas do Hospital Naval Marcílio Dias - IPB/HNMD, Rio de Janeiro, Brazil
| | - José Eduardo Ferreira Manso
- Departamento de Cirurgia, Faculdade de Medicina, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Vivaldo Moura Neto
- Instituto Estadual do Cérebro Paulo Niemeyer, Secretaria de Estado de Saúde, Rio de Janeiro, Brazil
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14
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Ioffe D, McSweeny M, Hall MJ. Precision Medicine in the Era of Genetic Testing: Microsatellite Instability Evolved. Clin Colon Rectal Surg 2024; 37:157-171. [PMID: 38617845 PMCID: PMC11007599 DOI: 10.1055/s-0043-1770385] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/16/2024]
Abstract
The recognized importance of microsatellite instability (MSI) in cancer has evolved considerably in the past 30 years. From its beginnings as a molecular predictor for Lynch syndrome, MSI first transitioned to a universal screening test in all colorectal and endometrial cancers, substantially increasing the identification of patients with Lynch syndrome among cancer patients. More recently, MSI has been shown to be a powerful biomarker of response to immune checkpoint blockade therapy across a diversity of tumor types, and in 2017 was granted Food and Drug Administration approval as the first tumor histology-agnostic biomarker for a cancer therapy. Focusing on colorectal cancer specifically, immune checkpoint blockade therapy has been shown to be highly effective in the treatment of both MSI-high (MSI-H) colon and rectal cancer, with data increasingly suggesting an early role for immune checkpoint blockade therapy in MSI-H colorectal tumors in the neoadjuvant setting, with the potential to avoid more toxic and morbid approaches using traditional chemotherapy, radiation therapy, and surgery. The success of MSI as an immune checkpoint blockade target has inspired ongoing vigorous research to identify new similar targets for immune checkpoint blockade therapy that may help to one day expand the reach of this revolutionary cancer therapy to a wider swath of patients and indications.
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Affiliation(s)
- Dina Ioffe
- Department of Clinical Genetics, Fox Chase Cancer Center, Philadelphia, Pennsylvania
| | - Michelle McSweeny
- Department of Clinical Genetics, Fox Chase Cancer Center, Philadelphia, Pennsylvania
| | - Michael J. Hall
- Department of Clinical Genetics, Fox Chase Cancer Center, Philadelphia, Pennsylvania
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15
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Chen DL, Chen N, Sheng H, Zhang DS. Circular RNA circNCOA3 promotes tumor progression and anti-PD-1 resistance in colorectal cancer. CANCER DRUG RESISTANCE (ALHAMBRA, CALIF.) 2024; 7:9. [PMID: 38510750 PMCID: PMC10951830 DOI: 10.20517/cdr.2023.151] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 12/07/2023] [Revised: 02/08/2024] [Accepted: 03/05/2024] [Indexed: 03/22/2024]
Abstract
Aim: Circular RNAs (circRNAs) have been found to be involved in tumor progression, but their role in colorectal cancer (CRC) immune escape remains to be elucidated. Methods: circRNAs differentially expressed in responsive and resistant CRC tissues to programmed cell death 1 (PD-1) antibody therapy were identified by microarray analysis. The clinical and pathological significance of circNCOA3 was validated in a separate cohort of CRC samples. The function of circNCOA3 was explored experimentally. RNA immunoprecipitation and luciferase activity assays were conducted to identify downstream targets of circNCOA3. Results: The circNCOA3 was markedly overexpressed in CRC samples resistant to PD-1 blockade. circNCOA3 expression was significantly correlated with adverse tumor phenotypes and poor outcomes in CRC patients. Knockdown of circNCOA3 expression markedly suppressed the proliferative and invasive capability of CRC cells. Moreover, knockdown of circNCOA3 increased the proportion of CD8+ T cells while decreasing the proportion of myeloid-derived suppressor cells (MDSCs). Knockdown of circNCOA3 inhibited tumor growth and increased the sensitivity to PD-1 antibody treatment in mouse tumor models. Further studies revealed that circNCOA3 acted as a competing endogenous RNA (ceRNA) for miR-203a-3p.1 to influence the level of CXCL1. Conclusion: Our findings indicate that circNCOA3 might be useful as a potential biomarker to predict the efficacy and prognosis of CRC patients treated with anti-PD-1 therapy.
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Affiliation(s)
- Dong-Liang Chen
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, Guangdong, China
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16
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Clerick J, Van Oosterwyck A, Carton S. Transforming the landscape of colorectal cancer treatment with immunotherapy: Evolution and future horizons. Cancer Treat Res Commun 2024; 39:100807. [PMID: 38461691 DOI: 10.1016/j.ctarc.2024.100807] [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: 07/08/2023] [Revised: 09/18/2023] [Accepted: 03/04/2024] [Indexed: 03/12/2024]
Abstract
Colorectal cancer (CRC) continues to be one of the most prevalent and lethal cancers worldwide. Over the past decades, immune checkpoint inhibitors (ICIs) have shown to significantly improve patient outcomes in mismatch repair-deficient metastasized CRC. However, widening the scope of this novel treatment modality has been the object of growing interest. This article will review several landmark trials, while exploring various aspects of this rapidly evolving field, including potential neoadjuvant (or even entirely nonsurgical) and adjuvant indications in localized disease. We will also discuss differences between management of rectal and colon cancer, current and expected challenges (eg. resistance, toxicities, pseudoprogression, biomarkers) and other future opportunities including combinations with other therapeutic agents and the role of ICIs in the treatment of both deficient as well as proficient mismatch repair (dMMR and pMMR respectively) CRC.
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Affiliation(s)
- Jan Clerick
- Department of Gastroenterology and Digestive Oncology, Imeldaziekenhuis, Bonheiden, Belgium
| | - Aude Van Oosterwyck
- Department of Gastroenterology and Digestive Oncology, Imeldaziekenhuis, Bonheiden, Belgium.
| | - Saskia Carton
- Department of Gastroenterology and Digestive Oncology, Imeldaziekenhuis, Bonheiden, Belgium
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17
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Gmeiner WH. Recent Advances in Therapeutic Strategies to Improve Colorectal Cancer Treatment. Cancers (Basel) 2024; 16:1029. [PMID: 38473386 PMCID: PMC10930828 DOI: 10.3390/cancers16051029] [Citation(s) in RCA: 17] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Revised: 02/24/2024] [Accepted: 02/29/2024] [Indexed: 03/14/2024] Open
Abstract
Colorectal cancer (CRC) is the second-leading cause of cancer-related mortality worldwide. CRC mortality results almost exclusively from metastatic disease (mCRC) for which systemic chemotherapy is often a preferred therapeutic option. Biomarker-based stratification of mCRC enables the use of precision therapy based on individual tumor mutational profiles. Activating mutations in the RAS/RAF/MAPK pathway downstream of EGFR signaling have, until recently, limited the use of EGFR-targeted therapies for mCRC; however, the development of anti-RAS and anti-RAF therapies together with improved strategies to limit compensatory signaling pathways is resulting in improved survival rates in several highly lethal mCRC sub-types (e.g., BRAF-mutant). The use of fluoropyrimidine (FP)-based chemotherapy regimens to treat mCRC continues to evolve contributing to improved long-term survival. Future advances in chemotherapy for mCRC will need to position development relative to the advances made in precision oncology.
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Affiliation(s)
- William H Gmeiner
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA
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18
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Takei S, Tanaka Y, Lin YT, Koyama S, Fukuoka S, Hara H, Nakamura Y, Kuboki Y, Kotani D, Kojima T, Bando H, Mishima S, Ueno T, Kojima S, Wakabayashi M, Sakamoto N, Kojima M, Kuwata T, Yoshino T, Nishikawa H, Mano H, Endo I, Shitara K, Kawazoe A. Multiomic molecular characterization of the response to combination immunotherapy in MSS/pMMR metastatic colorectal cancer. J Immunother Cancer 2024; 12:e008210. [PMID: 38336371 PMCID: PMC10860060 DOI: 10.1136/jitc-2023-008210] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/16/2024] [Indexed: 02/12/2024] Open
Abstract
BACKGROUND Immune checkpoint inhibitor (ICI) combinations represent an emerging treatment strategies in cancer. However, their efficacy in microsatellite stable (MSS) or mismatch repair-proficient (pMMR) colorectal cancer (CRC) is variable. Here, a multiomic characterization was performed to identify predictive biomarkers associated with patient response to ICI combinations in MSS/pMMR CRC for the further development of ICI combinations. METHODS Whole-exome sequencing, RNA sequencing, and multiplex fluorescence immunohistochemistry of tumors from patients with MSS/pMMR CRC, who received regorafenib plus nivolumab (REGONIVO) or TAS-116 plus nivolumab (TASNIVO) in clinical trials were conducted. Twenty-two and 23 patients without prior ICI from the REGONIVO and TASNIVO trials were included in this study. A biomarker analysis was performed using samples from each of these studies. RESULTS The epithelial-mesenchymal transition pathway and genes related to cancer-associated fibroblasts were upregulated in the REGONIVO responder group, and the G2M checkpoint pathway was upregulated in the TASNIVO responder group. The MYC pathway was upregulated in the REGONIVO non-responder group. Consensus molecular subtype 4 was significantly associated with response (p=0.035) and longer progression-free survival (p=0.006) in the REGONIVO trial. CD8+ T cells, regulatory T cells, and M2 macrophages density was significantly higher in the REGONIVO trial responders than in non-responders. Mutations in the POLE gene and patient response were significantly associated in the TASNIVO trial; however, the frequencies of other mutations or tumor mutational burden were not significantly different between responders and non-responders in either trial. CONCLUSIONS We identified molecular features associated with the response to the REGONIVO and TASNIVO, particularly those related to tumor microenvironmental factors. These findings are likely to contribute to the development of biomarkers to predict treatment efficacy for MSS/pMMR CRC and future immunotherapy combinations for treatment.
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Affiliation(s)
- Shogo Takei
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center-Hospital East, Kashiwa, Japan
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Yosuke Tanaka
- Division of Cellular Signaling, National Cancer Center Research Institute, Tokyo, Japan
| | - Yi-Tzu Lin
- Division of Cancer Immunology, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center-Hospital East, Kashiwa, Japan
| | - Shohei Koyama
- Division of Cancer Immunology, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center-Hospital East, Kashiwa, Japan
| | - Shota Fukuoka
- Department of Gastroenterology, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Hiroki Hara
- Department of Gastroenterology, Saitama Cancer Center, Kitaadachi-gun, Japan
| | - Yoshiaki Nakamura
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center-Hospital East, Kashiwa, Japan
| | - Yasutoshi Kuboki
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center-Hospital East, Kashiwa, Japan
| | - Daisuke Kotani
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center-Hospital East, Kashiwa, Japan
| | - Takashi Kojima
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center-Hospital East, Kashiwa, Japan
| | - Hideaki Bando
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center-Hospital East, Kashiwa, Japan
| | - Saori Mishima
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center-Hospital East, Kashiwa, Japan
| | - Toshihide Ueno
- Division of Cellular Signaling, National Cancer Center Research Institute, Tokyo, Japan
| | - Shinya Kojima
- Division of Cellular Signaling, National Cancer Center Research Institute, Tokyo, Japan
| | - Masashi Wakabayashi
- Biostatistics Division, Center for Research Administration and Support, National Cancer Center-Hospital East, Kashiwa, Chiba, Japan
| | - Naoya Sakamoto
- Department of Pathology and Clinical Laboratories, National Cancer Center-Hospital East, Kashiwa, Chiba, Japan
| | - Motohiro Kojima
- Department of Pathology and Clinical Laboratories, National Cancer Center-Hospital East, Kashiwa, Chiba, Japan
| | - Takeshi Kuwata
- Department of Pathology and Clinical Laboratories, National Cancer Center-Hospital East, Kashiwa, Chiba, Japan
- Department of Genetic Medicine and Services, National Cancer Center-Hospital East, Kashiwa, Chiba, Japan
| | - Takayuki Yoshino
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center-Hospital East, Kashiwa, Japan
| | - Hiroyoshi Nishikawa
- Division of Cancer Immunology, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center-Hospital East, Kashiwa, Japan
- Department of Immunology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Hiroyuki Mano
- Division of Cellular Signaling, National Cancer Center Research Institute, Tokyo, Japan
| | - Itaru Endo
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Kohei Shitara
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center-Hospital East, Kashiwa, Japan
- Department of Immunology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Akihito Kawazoe
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center-Hospital East, Kashiwa, Japan
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19
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Gu XY, Huo JL, Yu ZY, Jiang JC, Xu YX, Zhao LJ. Immunotherapy in hepatocellular carcinoma: an overview of immune checkpoint inhibitors, drug resistance, and adverse effects. ONCOLOGIE 2024; 26:9-25. [DOI: 10.1515/oncologie-2023-0412] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
Abstract
Abstract
Hepatocellular carcinoma (HCC) is a concerning liver cancer with rising incidence and mortality rates worldwide. The effectiveness of traditional therapies in managing advanced HCC is limited, necessitating the development of new therapeutic strategies. Immune checkpoint inhibitors (ICIs) have emerged as a promising strategy for HCC management. By preventing tumor cells from evading immune surveillance through immunological checkpoints, ICIs can restore the immune system’s ability to target and eliminate tumors. While ICIs show promise in enhancing the immune response against malignancies, challenges such as drug resistance and adverse reactions hinder their efficacy. To address these challenges, developing individualized ICI treatment strategies is critical. Combining targeted therapy and immunotherapy holds the potential for comprehensive therapeutic effects. Additionally, biomarker-based individualized ICI treatment strategies offer promise in predicting treatment response and guiding personalized patient care. Future research should explore emerging ICI treatment methods to optimize HCC immunotherapy. This review provides an overview of ICIs as a new treatment for HCC, demonstrating some success in promoting the tumor immune response. However, drug resistance and adverse reactions remain important considerations that must be addressed. As tailored treatment plans evolve, the prospect of immunotherapy for HCC is expected to grow, offering new opportunities for improved patient outcomes.
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Affiliation(s)
- Xuan-Yu Gu
- Department of General Surgery , Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University , Zunyi , China
| | - Jin-Long Huo
- Department of General Surgery , Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University , Zunyi , China
| | - Zhi-Yong Yu
- Department of General Surgery , Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University , Zunyi , China
| | - Ji-Chang Jiang
- Department of General Surgery , Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University , Zunyi , China
| | - Ya-Xuan Xu
- Department of General Surgery , Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University , Zunyi , China
| | - Li-Jin Zhao
- Department of General Surgery , Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University , Zunyi , China
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20
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Faghfuri E. Recent advances in personalized cancer immunotherapy with immune checkpoint inhibitors, T cells and vaccines. Per Med 2024; 21:45-57. [PMID: 38088165 DOI: 10.2217/pme-2023-0054] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2024]
Abstract
The results of genomic and molecular profiling of cancer patients can be effectively applied to immunotherapy agents, including immune checkpoint inhibitors, to select the most appropriate treatment. In addition, accurate prediction of neoantigens facilitates the development of individualized cancer vaccines and T-cell therapy. This review summarizes the biomarker(s) predicting responses to immune checkpoint inhibitors and focuses on current strategies to identify and isolate neoantigen-reactive T cells as well as the clinical development of neoantigen-based therapeutics. The results suggest that maximal T-cell stimulation and expansion can be achieved with combination therapies that enhance antigen-presenting cells' function and optimal T-cell priming in lymph nodes.
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Affiliation(s)
- Elnaz Faghfuri
- Digestive Disease Research Center, Ardabil University of Medical Sciences, Ardabil, 5613658115, Iran
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21
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Veen T, Kanani A, Lea D, Søreide K. Clinical trials of neoadjuvant immune checkpoint inhibitors for early-stage operable colon and rectal cancer. Cancer Immunol Immunother 2023; 72:3135-3147. [PMID: 37528319 PMCID: PMC10491705 DOI: 10.1007/s00262-023-03480-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2023] [Accepted: 06/08/2023] [Indexed: 08/03/2023]
Abstract
BACKGROUND Immune checkpoint inhibitors (ICI) have become first-line treatment for metastatic colorectal cancer (CRC) with deficient mismatch repair (dMMR). Despite the remarkable response reported in preliminary trials, the role of ICI in patients with early-stage, operable CRC remains unclear. The aim of this study was to investigate trials on neoadjuvant ICI in operable CRC. MATERIALS AND METHODS Scoping review of clinical trial registries (Clinicaltrials.gov and EU clinical trial registers) and PubMed/Medline database of trials on neoadjuvant ICI for operable CRC was done up to December 2022. RESULTS Some 40 trials investigating neoadjuvant ICI for early-stage, operable CRC were identified, including five published trials and three conference abstracts. Preclinical phase I/II trial predominated with only three clinical phase III trials. Few trials investigated neoadjuvant ICI as the only intervention (monotherapy). Trials in rectal cancer were designed for combined ICI with chemo(radio)therapy, only 8 trials stating an MSI/dMMR status for inclusion, one designed for MSS/pMMR only and, the rest agnostic for MMR status. Thirty-eight (95%) trials investigated programmed cell death protein 1 (PD-1) or programmed cell death ligand 1 (PD-L1) inhibitors. PD-1/PD-L1 inhibitors were combined with vascular endothelial growth factor (VEGF) inhibitor or with cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) inhibitor, in two trials each, respectively. Pathological complete response as primary outcome after surgery was the most frequently used study endpoint. In rectal cancer, six trials included a "watch and wait" strategy for patients with complete clinical response. No "watch and wait" study design for colon cancer after neoadjuvant ICI were identified. CONCLUSION High response rates from neoadjuvant ICI in early-stage colon and rectal cancer are reported in phase I/II studies. Contemporary trial designs are heterogeneous, with few comparable inclusion criteria, use of several drug combinations and durations and, wide variation of endpoints reported. Harmonizing clinical and translational aspects including survival data is needed for improved future trial designs with clinical impact.
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Affiliation(s)
- Torhild Veen
- Department of Gastrointestinal Surgery, Stavanger University Hospital, Stavanger, Norway
- Gastrointestinal Translational Research Unit, Laboratory for Molecular Medicine, Stavanger University Hospital, Stavanger, Norway
| | - Arezo Kanani
- Department of Gastrointestinal Surgery, Stavanger University Hospital, Stavanger, Norway
- Gastrointestinal Translational Research Unit, Laboratory for Molecular Medicine, Stavanger University Hospital, Stavanger, Norway
| | - Dordi Lea
- Gastrointestinal Translational Research Unit, Laboratory for Molecular Medicine, Stavanger University Hospital, Stavanger, Norway
- Department of Pathology, Stavanger University Hospital, Stavanger, Norway
| | - Kjetil Søreide
- Department of Gastrointestinal Surgery, Stavanger University Hospital, Stavanger, Norway.
- Gastrointestinal Translational Research Unit, Laboratory for Molecular Medicine, Stavanger University Hospital, Stavanger, Norway.
- Department of Clinical Medicine, University of Bergen, Bergen, Norway.
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22
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Ros J, Baraibar I, Saoudi N, Rodriguez M, Salvà F, Tabernero J, Élez E. Immunotherapy for Colorectal Cancer with High Microsatellite Instability: The Ongoing Search for Biomarkers. Cancers (Basel) 2023; 15:4245. [PMID: 37686520 PMCID: PMC10486610 DOI: 10.3390/cancers15174245] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2023] [Revised: 08/22/2023] [Accepted: 08/23/2023] [Indexed: 09/10/2023] Open
Abstract
Microsatellite instability (MSI) is a biological condition associated with inflamed tumors, high tumor mutational burden (TMB), and responses to immune checkpoint inhibitors. In colorectal cancer (CRC), MSI tumors are found in 5% of patients in the metastatic setting and 15% in early-stage disease. Following the impressive clinical activity of immune checkpoint inhibitors in the metastatic setting, associated with deep and long-lasting responses, the development of immune checkpoint inhibitors has expanded to early-stage disease. Several phase II trials have demonstrated a high rate of pathological complete responses, with some patients even spared from surgery. However, in both settings, not all patients respond and some responses are short, emphasizing the importance of the ongoing search for accurate biomarkers. While various biomarkers of response have been evaluated in the context of MSI CRC, including B2M and JAK1/2 mutations, TMB, WNT pathway mutations, and Lynch syndrome, with mixed results, liver metastases have been associated with a lack of activity in such strategies. To improve patient selection and treatment outcomes, further research is required to identify additional biomarkers and refine existing ones. This will allow for the development of personalized treatment approaches and the integration of novel therapeutic strategies for MSI CRC patients with liver metastases.
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Affiliation(s)
- Javier Ros
- Medical Oncology Department, Vall d’Hebron University Hospital, 08035 Barcelona, Spain; (J.R.); (I.B.); (N.S.); (M.R.); (F.S.); (J.T.)
- Vall d’Hebron Institute of Oncology, 08035 Barcelona, Spain
| | - Iosune Baraibar
- Medical Oncology Department, Vall d’Hebron University Hospital, 08035 Barcelona, Spain; (J.R.); (I.B.); (N.S.); (M.R.); (F.S.); (J.T.)
- Vall d’Hebron Institute of Oncology, 08035 Barcelona, Spain
| | - Nadia Saoudi
- Medical Oncology Department, Vall d’Hebron University Hospital, 08035 Barcelona, Spain; (J.R.); (I.B.); (N.S.); (M.R.); (F.S.); (J.T.)
- Vall d’Hebron Institute of Oncology, 08035 Barcelona, Spain
| | - Marta Rodriguez
- Medical Oncology Department, Vall d’Hebron University Hospital, 08035 Barcelona, Spain; (J.R.); (I.B.); (N.S.); (M.R.); (F.S.); (J.T.)
- Vall d’Hebron Institute of Oncology, 08035 Barcelona, Spain
| | - Francesc Salvà
- Medical Oncology Department, Vall d’Hebron University Hospital, 08035 Barcelona, Spain; (J.R.); (I.B.); (N.S.); (M.R.); (F.S.); (J.T.)
- Vall d’Hebron Institute of Oncology, 08035 Barcelona, Spain
| | - Josep Tabernero
- Medical Oncology Department, Vall d’Hebron University Hospital, 08035 Barcelona, Spain; (J.R.); (I.B.); (N.S.); (M.R.); (F.S.); (J.T.)
- Vall d’Hebron Institute of Oncology, 08035 Barcelona, Spain
| | - Elena Élez
- Medical Oncology Department, Vall d’Hebron University Hospital, 08035 Barcelona, Spain; (J.R.); (I.B.); (N.S.); (M.R.); (F.S.); (J.T.)
- Vall d’Hebron Institute of Oncology, 08035 Barcelona, Spain
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23
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Lutfi A, Afghan MK, Kasi PM. Circulating Tumor DNA Response and Minimal Residual Disease Assessment in DNA Polymerase Epsilon-Mutated Colorectal Cancer Undergoing Immunotherapy. Cureus 2023; 15:e43391. [PMID: 37593074 PMCID: PMC10428188 DOI: 10.7759/cureus.43391] [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] [Accepted: 08/12/2023] [Indexed: 08/19/2023] Open
Abstract
Exonuclease domain mutation (EDM) in polymerase epsilon (POLE)-mutated colorectal cancer patients is characterized by specific clinical features and a very high tumor mutation burden (TMB). The therapeutic effectiveness of immune checkpoint inhibitors (ICIs) for the treatment of colorectal cancer in patients with POLE mutations is poorly defined. Our case represents a young-onset colon cancer patient who has had a continued response to programmed cell death protein 1 (PD1) blockade alongside clearance of circulating tumor DNA (ctDNA) using a tumor-informed approach. Utilizing ctDNA kinetics to assess minimal residual disease (MRD) in the context of colorectal cancer is a very important topic. Furthermore, utilizing ctDNA kinetics in response to immunotherapy is something that is relevant to all tumor types undergoing immunotherapy. Recently, several landmark articles have proposed this as a promising approach. There is, however, limited information in the literature showing the feasibility of such an approach. Our case report is going to be of value, both from a scientific as well as a clinical standpoint. This is particularly relevant given the rise of colorectal cancers in young individuals.
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Affiliation(s)
- Areeb Lutfi
- Oncology, Weill Cornell Medicine, New York, USA
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24
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Xu Y, Ma K, Zhang F, Ma M, Hong L, Wang J, Li S, Sun P, Wang J, Wei S. Association between baseline C‑reactive protein level and survival outcomes for cancer patients treated with immunotherapy: A meta‑analysis. Exp Ther Med 2023; 26:361. [PMID: 37408861 PMCID: PMC10318603 DOI: 10.3892/etm.2023.12060] [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: 09/03/2022] [Accepted: 03/16/2023] [Indexed: 07/07/2023] Open
Abstract
The prognostic impact of baseline C-reactive protein (CRP) in patients with cancer receiving immune checkpoint inhibitors (ICIs) is unclear. The present meta-analysis aimed to review the prognostic value of baseline C-reactive protein (CRP) levels for patients with cancer receiving immunotherapy. Electronic databases, including PubMed, EMbase, Cochrane Library, Web of Science, Chinese National Knowledge Infrastructure, WanFang, Chinese Literature Biomedical Database and Weipu Database, were used to identify cohort studies on the relationship between the baseline CRP levels and ICI survival outcomes from inception to November 2020. Literature screening, data extraction and quality evaluation of studies were independently performed by two reviewers. Subsequently, a meta-analysis was performed using STATA 14.0. A total of 13 cohort studies comprising 2,387 patients with cancer were included in the present meta-analysis. The results indicated that high baseline CRP levels (serum CRP measured within 2 weeks before ICI treatment) were associated with low overall survival (OS) and progression-free survival (PFS) rate among patients treated with ICIs. The subgroup analysis based on cancer type showed that high baseline CRP levels were associated with poor survival outcomes of multiple types of cancer, such as non-small cell lung cancer (6/13; 46.2%), melanoma (2/13; 15.4%), renal cell (3/13; 23.0%) and urothelial carcinoma (2/13; 15.4%). Similar results were observed in subgroup analysis based on the CRP cut-off value of 10 mg/l. In addition, a higher mortality risk was reported in patients with cancer and CRP ≥10 mg/l (hazard ratio, 2.76; 95% CI, 1.70-4.48; P<0.001). Compared with patients with low baseline CRP levels, increased baseline CRP levels were associated with low OS and PFS rate in patients with cancer receiving ICIs. Furthermore, CRP ≥10 mg/l indicated a worse prognosis. Therefore, baseline CRP levels may serve as a marker for the prognosis of patients with certain types of solid tumor treated with ICIs. Due to the limited quality and quantity of included studies, more prospective well-designed studies are required to verify the present findings.
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Affiliation(s)
- Yu Xu
- Department of Medical Oncology, Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, P.R. China
| | - Ke Ma
- Department of Pharmacology, School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, P.R. China
| | - Fan Zhang
- Department of Medical Oncology, Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, P.R. China
| | - Minting Ma
- Department of Medical Oncology, Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, P.R. China
| | - Lei Hong
- Department of Medical Oncology, Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, P.R. China
| | - Jing Wang
- Department of Medical Oncology, Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, P.R. China
| | - Suping Li
- Department of Medical Oncology, Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, P.R. China
| | - Panpan Sun
- Department of Medical Oncology, Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, P.R. China
| | - Junyan Wang
- Department of Medical Oncology, Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, P.R. China
| | - Suju Wei
- Department of Medical Oncology, Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, P.R. China
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25
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Li C, Wirth U, Schardey J, Ehrlich-Treuenstätt VV, Bazhin AV, Werner J, Kühn F. An immune-related gene prognostic index for predicting prognosis in patients with colorectal cancer. Front Immunol 2023; 14:1156488. [PMID: 37483596 PMCID: PMC10358773 DOI: 10.3389/fimmu.2023.1156488] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Accepted: 06/13/2023] [Indexed: 07/25/2023] Open
Abstract
Background Colorectal cancer (CRC) is one of the most common solid malignant burdens worldwide. Cancer immunology and immunotherapy have become fundamental areas in CRC research and treatment. Currently, the method of generating Immune-Related Gene Prognostic Indices (IRGPIs) has been found to predict patient prognosis as an immune-related prognostic biomarker in a variety of tumors. However, their role in patients with CRC remains mostly unknown. Therefore, we aimed to establish an IRGPI for prognosis evaluation in CRC. Methods RNA-sequencing data and clinical information of CRC patients were retrieved from The Cancer Genome Atlas (TCGA) and The Gene Expression Omnibus (GEO) databases as training and validation sets, respectively. Immune-related gene data was obtained from the ImmPort and InnateDB databases. The weighted gene co-expression network analysis (WGCNA) was used to identify hub immune-related genes. An IRGPI was then constructed using Cox regression methods. Based on the median risk score of IRGPI, patients could be divided into high-risk and low-risk groups. To further investigate the immunologic differences, Gene set variation analysis (GSVA) studies were conducted. In addition, immune cell infiltration and related functional analysis were used to identify the differential immune cell subsets and related functional pathways. Results We identified 49 immune-related genes associated with the prognosis of CRC, 17 of which were selected for an IRGPI. The IRGPI model significantly differentiates the survival rates of CRC patients in the different groups. The IRGPI as an independent prognostic factor significantly correlates with clinico-pathological factors such as age and tumor stage. Furthermore, we developed a nomogram to improve the clinical utility of the IRGPI score. Immuno-correlation analysis in different IRGPI groups revealed distinct immune cell infiltration (CD4+ T cells resting memory) and associated pathways (macrophages, Type I IFNs responses, iDCs.), providing new insights into the tumor microenvironment. At last, drug sensitivity analysis revealed that the high-risk IRGPI group was sensitive to 11 and resistant to 15 drugs. Conclusion Our study established a promising immune-related risk model for predicting survival in CRC patients. This could help to better understand the correlation between immunity and the prognosis of CRC providing a new perspective for personalized treatment of CRC.
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Affiliation(s)
- Chao Li
- Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Ulrich Wirth
- Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Josefine Schardey
- Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, Munich, Germany
| | | | - Alexandr V. Bazhin
- Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, Munich, Germany
- German Cancer Consortium (DKTK), Munich, Germany
- Bavarian Cancer Research Center (BZKF), Munich, Germany
| | - Jens Werner
- Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, Munich, Germany
- German Cancer Consortium (DKTK), Munich, Germany
- Bavarian Cancer Research Center (BZKF), Munich, Germany
| | - Florian Kühn
- Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, Munich, Germany
- German Cancer Consortium (DKTK), Munich, Germany
- Bavarian Cancer Research Center (BZKF), Munich, Germany
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26
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Duggan WP, Kisakol B, O'Connell E, Matveeva A, O'Grady T, McDonough E, Lindner AU, McNamara D, Longley D, Ginty F, Burke JP, Prehn JHM. Multiplexed Immunofluorescence Imaging Reveals an Immune-Rich Tumor Microenvironment in Mucinous Rectal Cancer Characterized by Increased Lymphocyte Infiltration and Enhanced Programmed Cell Death Protein 1 Expression. Dis Colon Rectum 2023; 66:914-922. [PMID: 36525395 PMCID: PMC10591203 DOI: 10.1097/dcr.0000000000002624] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
BACKGROUND Mucinous rectal cancer is associated with a higher incidence of microsatellite instability and a poorer response to neoadjuvant chemoradiotherapy compared to other subtypes of rectal adenocarcinoma. Immune checkpoint inhibitors are an emerging family of anticancer therapeutics associated with highly variable outcomes in colorectal cancer. Although the immune landscape of mucinous rectal cancer has not been fully explored, the presence of mucin is thought to act as a barrier preventing immune-cell infiltration. OBJECTIVE The aim of this study was to determine the immune properties of mucinous rectal cancer and investigate the degree of lymphocyte infiltration in this cohort. DESIGN This is a retrospective cohort study that involved multiplexed immunofluorescence staining of tumor microarrays. SETTINGS Samples originated from a single university teaching hospital. PATIENTS Our cohort included 15 cases of mucinous and 43 cases of nonmucinous rectal cancer. MAIN OUTCOME MEASURES Immune cells were classified and quantified. Immune-cell counts were compared between mucinous and nonmucinous cohorts. Immune marker expression within tumor epithelial tissue was evaluated to determine the degree of lymphocyte infiltration. RESULTS Cytotoxic ( p = 0.022) and regulatory T cells ( p = 0.010) were found to be overrepresented in the mucinous cohort compared to the nonmucinous group. Programmed cell death protein 1 expression was also found to be significantly greater in the mucinous group ( p = 0.001). CD3 ( p = 0.001) and CD8 ( p = 0.054) expressions within the tumor epithelium were also higher in the mucinous group, suggesting adequate immune infiltration despite the presence of mucin. In our analysis, microsatellite instability status was not a predictor of immune marker expression. LIMITATIONS The relatively small size of the cohort. CONCLUSIONS Mucinous rectal cancer is associated with an immune-rich tumor microenvironment, which was not associated with microsatellite instability status. See Video Abstract at http://links.lww.com/DCR/C65 . IMGENES DE INMUNOFLUORESCENCIA MULTIPLEXADAS REVELAN UN MICROAMBIENTE TUMORAL RICO EN INMUNIDAD EN EL CNCER RECTAL MUCINOSO CARACTERIZADO POR UNA MAYOR INFILTRACIN DE LINFOCITOS Y UNA EXPRESIN MEJORADA DE PD ANTECEDENTES:El cáncer rectal mucinoso se asocia con una mayor incidencia de inestabilidad de microsatélites y una peor respuesta a la quimiorradioterapia neoadyuvante en comparación con otros subtipos de adenocarcinoma rectal. Los inhibidores de puntos de control inmunitarios son una familia emergente de tratamientos contra el cáncer asociados con resultados muy variables en el cáncer colorrectal. Aunque el panorama inmunitario del cáncer rectal mucinoso no se ha explorado completamente, se cree que la presencia de mucina actúa como una barrera que previene la infiltración de células inmunitarias.OBJETIVO:El objetivo de este estudio fue determinar las propiedades inmunes del cáncer de recto mucinoso e investigar el grado de infiltración de linfocitos en esta cohorte.DISEÑO:Este es un estudio de cohorte retrospectivo que involucró la tinción de inmunofluorescencia multiplexada de micromatrices tumorales.AJUSTES:Las muestras se originaron en un solo hospital docente universitario.PACIENTES:Nuestra cohorte incluyó 15 casos de cáncer de recto mucinoso y 43 casos de cáncer de recto no mucinosoPRINCIPALES MEDIDAS DE RESULTADO:Las células inmunitarias se clasificaron y cuantificaron. Se compararon los recuentos de células inmunitarias entre cohortes mucinosas y no mucinosas. Se evaluó la expresión del marcador inmunitario dentro del tejido epitelial tumoral para determinar el grado de infiltración de linfocitos.RESULTADOS:Se encontró que las células T citotóxicas ( p = 0,022) y reguladoras ( p = 0,010) estaban sobrerrepresentadas en la cohorte mucinosa en comparación con el grupo no mucinoso. También se encontró que la expresión de PD-1 era significativamente mayor en el grupo mucinoso ( p = 0,001). La expresión de CD3 ( p = 0,001) y CD8 ( p = 0,054) dentro del epitelio tumoral también fue mayor en el grupo mucinoso, lo que sugiere una infiltración inmunitaria adecuada a pesar de la presencia de mucina. En nuestro análisis, no se encontró que el estado de inestabilidad de los microsatélites sea un predictor de la expresión del marcador inmunitario.LIMITACIONES:El tamaño relativamente pequeño de la cohorte.CONCLUSIONES:El cáncer rectal mucinoso se asocia con un microambiente tumoral rico en inmunidad, que no se asoció con el estado de inestabilidad de microsatélites. Consulte el Video del Resumen en http://links.lww.com/DCR/C65 . (Traducción- Dr. Yesenia Rojas-Khalil ).
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Affiliation(s)
- William P Duggan
- Department of Colorectal Surgery, Beaumont Hospital, Dublin, Ireland
- Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland
| | - Batuhan Kisakol
- Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland
- Centre for Systems Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland
| | - Emer O'Connell
- Department of Colorectal Surgery, Beaumont Hospital, Dublin, Ireland
- Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland
| | - Anna Matveeva
- Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland
- Centre for Systems Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland
| | - Tony O'Grady
- Department of Pathology, Beaumont Hospital, Dublin, Ireland
| | | | - Andreas U Lindner
- Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland
- Centre for Systems Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland
| | - Deborah McNamara
- Department of Colorectal Surgery, Beaumont Hospital, Dublin, Ireland
- Department of Surgery, Royal College of Surgeons in Ireland, Dublin, Ireland
| | - Daniel Longley
- Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, Northern Ireland, United Kingdom
| | | | - John P Burke
- Department of Colorectal Surgery, Beaumont Hospital, Dublin, Ireland
- Department of Surgery, Royal College of Surgeons in Ireland, Dublin, Ireland
| | - Jochen H M Prehn
- Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland
- Centre for Systems Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland
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Kyriazopoulou E, Giamarellos-Bourboulis EJ, Akinosoglou K. Biomarkers to guide immunomodulatory treatment: where do we stand? Expert Rev Mol Diagn 2023; 23:945-958. [PMID: 37691280 DOI: 10.1080/14737159.2023.2258063] [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: 07/09/2023] [Revised: 08/20/2023] [Accepted: 09/08/2023] [Indexed: 09/12/2023]
Abstract
INTRODUCTION This review summarizes current progress in the development of biomarkers to guide immunotherapy in oncology, rheumatology, and critical illness. AREAS COVERED An extensive literature search was performed about biomarkers classifying patients' immune responses to guide immunotherapy in oncology, rheumatology, and critical illness. Surface markers, such as programmed death-ligand 1 (PD-L1), genetic biomarkers, such as tumor mutation load, and circulating tumor DNA are biomarkers associated with the effectiveness of immunotherapy in oncology. Genomics, metabolomics, and proteomics play a crucial role in selecting the most suitable therapeutic options for rheumatologic patients. Phenotypes and endotypes are a promising approach to detect critically ill patients with hyper- or hypo-inflammation. Sepsis trials using biomarkers such as ferritin, lymphopenia, HLA-DR expression on monocytes and PD-L1 to guide immunotherapy have been already conducted or are currently ongoing. Immunotherapy in COVID-19 pneumonia, guided by C-reactive protein and soluble urokinase plasminogen activator receptor (suPAR) has improved patient outcomes globally. More research is needed into immunotherapy in other critical conditions. EXPERT OPINION Targeted immunotherapy has improved outcomes in oncology and rheumatology, paving the way for precision medicine in the critically ill. Transcriptomics will play a crucial role in detecting the most suitable candidates for immunomodulation.
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Affiliation(s)
- Evdoxia Kyriazopoulou
- 4th Department of Internal Medicine, National and Kapodistrian University of Athens, Athens, Greece
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28
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Bikhchandani M, Amersi F, Hendifar A, Gangi A, Osipov A, Zaghiyan K, Atkins K, Cho M, Aguirre F, Hazelett D, Alvarez R, Zhou L, Hitchins M, Gong J. POLE-Mutant Colon Cancer Treated with PD-1 Blockade Showing Clearance of Circulating Tumor DNA and Prolonged Disease-Free Interval. Genes (Basel) 2023; 14:1054. [PMID: 37239414 PMCID: PMC10218075 DOI: 10.3390/genes14051054] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Revised: 04/28/2023] [Accepted: 05/04/2023] [Indexed: 05/28/2023] Open
Abstract
Colon cancer with high microsatellite instability is characterized by a high tumor mutational burden and responds well to immunotherapy. Mutations in polymerase ɛ, a DNA polymerase involved in DNA replication and repair, are also associated with an ultra-mutated phenotype. We describe a case where a patient with POLE-mutated and hypermutated recurrent colon cancer was treated with pembrolizumab. Treatment with immunotherapy in this patient also led to the clearance of circulating tumor DNA (ctDNA). ctDNA is beginning to emerge as a marker for minimal residual disease in many solid malignancies, including colon cancer. Its clearance with treatment suggests that the selection of pembrolizumab on the basis of identifying a POLE mutation on next-generation sequencing may increase disease-free survival in this patient.
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Affiliation(s)
- Mihir Bikhchandani
- Department of Hematology and Oncology, Kaiser Permanente Los Angeles Medical Center, Los Angeles, CA 90027, USA
| | - Farin Amersi
- Department of Surgery, Division of Surgical Oncology, Samuel Oschin Comprehensive Cancer Institute, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Andrew Hendifar
- Department of Medicine, Division of Hematology and Oncology, Samuel Oschin Comprehensive Cancer Institute, Cedars Sinai Medical Center, 8700 Beverly Blvd, AC 1042B, Los Angeles, CA 90048, USA
| | - Alexandra Gangi
- Department of Surgery, Division of Surgical Oncology, Samuel Oschin Comprehensive Cancer Institute, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Arsen Osipov
- Department of Medicine, Division of Hematology and Oncology, Samuel Oschin Comprehensive Cancer Institute, Cedars Sinai Medical Center, 8700 Beverly Blvd, AC 1042B, Los Angeles, CA 90048, USA
| | - Karen Zaghiyan
- Department of Surgery, Division of Surgical Oncology, Samuel Oschin Comprehensive Cancer Institute, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Katelyn Atkins
- Department of Radiation Oncology, Samuel Oschin Comprehensive Cancer Institute, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA
| | - May Cho
- Department of Medicine, Division of Hematology and Oncology, University of California Irvine, Irvine, CA 92868, USA
| | - Francesca Aguirre
- Department of Biomedical Sciences, Cedars-Sinai, Los Angeles, CA 90048, USA
| | - Dennis Hazelett
- Department of Biomedical Sciences, Cedars-Sinai, Los Angeles, CA 90048, USA
| | - Rocio Alvarez
- Department of Biomedical Sciences, Cedars-Sinai, Los Angeles, CA 90048, USA
| | - Lisa Zhou
- Department of Biomedical Sciences, Cedars-Sinai, Los Angeles, CA 90048, USA
| | - Megan Hitchins
- Department of Biomedical Sciences, Cedars-Sinai, Los Angeles, CA 90048, USA
| | - Jun Gong
- Department of Medicine, Division of Hematology and Oncology, Samuel Oschin Comprehensive Cancer Institute, Cedars Sinai Medical Center, 8700 Beverly Blvd, AC 1042B, Los Angeles, CA 90048, USA
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Alese OB, Wu C, Chapin WJ, Ulanja MB, Zheng-Lin B, Amankwah M, Eads J. Update on Emerging Therapies for Advanced Colorectal Cancer. Am Soc Clin Oncol Educ Book 2023; 43:e389574. [PMID: 37155942 DOI: 10.1200/edbk_389574] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/10/2023]
Abstract
Colorectal cancer (CRC) is the third most common malignancy worldwide. It is projected to increase by 3.2 million new cases and account for 1.6 million deaths by 2040. Mortality is largely due to limited treatment options for patients who present with advanced disease. Thus, the development of effective and tolerable therapies is crucial. Chemotherapy has been the backbone of systemic treatment of advanced CRC, but utility has been limited because of invariable resistance to therapy, narrow mechanisms of action, and unfavorable toxicity profile. Tumors that are mismatch repair-deficient have demonstrated remarkable response to immune checkpoint inhibitor therapy. However, most CRC tumors are mismatch repair-proficient and represent an unmet medical need. Although ERBB2 amplification occurs only in a few cases, it is associated with left-sided tumors and a higher incidence of brain metastasis. Numerous combinations of HER2 inhibitors have demonstrated efficacy, and antibody-drug conjugates against HER2 represent innovative strategies in this area. The KRAS protein has been classically considered undruggable. Fortunately, new agents targeting KRAS G12C mutation represent a paradigm shift in the management of affected patients and could lead the advancement in drug development for the more common KRAS mutations. Furthermore, aberrant DNA damage response is present in 15%-20% of CRCs, and emerging innovative combinations with poly (ADP-ribose) polymerase (PARP) inhibitors could improve the current therapeutic landscape. Multiple novel biomarker-driven approaches in the management of patients with advanced CRC tumors are reviewed in this article.
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Affiliation(s)
- Olatunji B Alese
- Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA
| | | | - William J Chapin
- Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA
| | - Mark B Ulanja
- Christus Ochsner St Patrick Hospital, Lake Charles, LA
| | | | | | - Jennifer Eads
- Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA
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Nikoo M, Hassan ZF, Mardasi M, Rostamnezhad E, Roozbahani F, Rahimi S, Mohammadi J. Hepatocellular carcinoma (HCC) immunotherapy by anti-PD-1 monoclonal antibodies: A rapidly evolving strategy. Pathol Res Pract 2023; 247:154473. [PMID: 37207558 DOI: 10.1016/j.prp.2023.154473] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2023] [Revised: 04/16/2023] [Accepted: 04/18/2023] [Indexed: 05/21/2023]
Abstract
Hepatocellular carcinoma (HCC) is one of the deadliest cancers in the world, with a high relapse rate. Delayed symptom onset observed in 70-80% of patients leads to diagnosis in advanced stages commonly associated with chronic liver disease. Programmed cell death protein 1 (PD-1) blockade therapy has recently emerged as a promising therapeutic option in the clinical management of several advanced malignancies, including HCC, due to the activation of exhausted tumor-infiltrating lymphocytes and improved outcomes of T-cell function. However, many people with HCC do not respond to PD-1 blockade therapy, and the diversity of immune-related adverse events (irAEs) restricts their clinical utility. Therefore, numerous effective combinatory strategies, including combinations with anti-PD-1 antibodies and other therapeutic methods ranging from chemotherapy to targeted therapies, are evolving to improve therapeutic outcomes and evoke synergistic anti-tumor impressions in patients with advanced HCC. Unfortunately, combined therapy may have more side effects than single-agent treatment. Nonetheless, identifying appropriate predictive biomarkers can aid in managing potential immune-related adverse events by distinguishing patients who respond best to PD-1 inhibitors as single agents or in combination strategies. In the present review, we summarize the therapeutic potential of PD-1 blockade therapy for advanced HCC patients. Besides, a glimpse of the pivotal predictive biomarkers influencing a patient's response to anti-PD-1 antibodies will be provided.
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Affiliation(s)
- Marzieh Nikoo
- Department of Immunology, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | | | - Mahsa Mardasi
- Biotechnology Department, Faculty of Life Sciences and Biotechnology, Shahid Beheshti University G. C., Evin, Tehran, Iran
| | - Elmira Rostamnezhad
- Department of Molecular Genetics, Faculty of Advanced Science and Technology, Tehran Medical Science, Islamic Azad University, Tehran, Iran
| | - Fatemeh Roozbahani
- Department of Microbiology and Virology, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
| | - Sahel Rahimi
- Industrial and Environmental Biotechnology Department, National Institute of Genetic Engineering and Biotechnology(NIGEB), Tehran, Iran
| | - Javad Mohammadi
- Department of Life Science Engineering, Faculty of New Sciences and Technologies, University of Tehran, Tehran, Iran.
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31
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Yu SJ. Immunotherapy for hepatocellular carcinoma: Recent advances and future targets. Pharmacol Ther 2023; 244:108387. [PMID: 36948423 DOI: 10.1016/j.pharmthera.2023.108387] [Citation(s) in RCA: 30] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Revised: 02/12/2023] [Accepted: 03/15/2023] [Indexed: 03/24/2023]
Abstract
Immunotherapy is a promising approach to treating various types of cancers, including hepatocellular carcinoma (HCC). While single immunotherapy drugs show limited effectiveness on a small subset of patients, the combination of the anti PD-L1 atezolizumab and anti-vascular endothelial growth factor bevacizumab has shown significant improvement in survival compared to sorafenib as a first-line treatment. However, the current treatment options still have a low success rate of about 30%. Thus, more effective treatments for HCC are urgently required. Several novel immunotherapeutic methods, including the use of novel immune checkpoint inhibitors, innovative immune cell therapies like chimeric antigen receptor T cells (CAR-T), TCR gene-modified T cells and stem cells, as well as combination strategies are being tested in clinical trials for the treatment of HCC. However, some crucial issues still exist such as the presence of heterogeneous antigens in solid tumors, the immune-suppressive environment within tumors, the risk of on-target/off-tumor, infiltrating CAR-T cells, immunosuppressive checkpoint molecules, and cytokines. Overall, immunotherapy is on the brink of major advancements in the fight against HCC.
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Affiliation(s)
- Su Jong Yu
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.
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32
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Mohd Yunos RI, Ab Mutalib NS, Khoo JS, Saidin S, Ishak M, Syafruddin SE, Tieng FYF, Md Yusof NF, Abd Razak MR, Mahamad Nadzir N, Abu N, Rose IM, Sagap I, Mazlan L, Jamal R. Whole genome sequencing of Malaysian colorectal cancer patients reveals specific druggable somatic mutations. Front Mol Biosci 2023; 9:997747. [PMID: 36866106 PMCID: PMC9972984 DOI: 10.3389/fmolb.2022.997747] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Accepted: 09/20/2022] [Indexed: 02/16/2023] Open
Abstract
The incidences of colorectal cancer (CRC) are continuously increasing in some areas of the world, including Malaysia. In this study, we aimed to characterize the landscape of somatic mutations using the whole-genome sequencing approach and identify druggable somatic mutations specific to Malaysian patients. Whole-genome sequencing was performed on the genomic DNA obtained from 50 Malaysian CRC patients' tissues. We discovered the top significantly mutated genes were APC, TP53, KRAS, TCF7L2 and ACVR2A. Four novel, non-synonymous variants were identified in three genes, which were KDM4E, MUC16 and POTED. At least one druggable somatic alteration was identified in 88% of our patients. Among them were two frameshift mutations in RNF43 (G156fs and P192fs) predicted to have responsive effects against the Wnt pathway inhibitor. We found that the exogenous expression of this RNF43 mutation in CRC cells resulted in increased cell proliferation and sensitivity against LGK974 drug treatment and G1 cell cycle arrest. In conclusion, this study uncovered our local CRC patients' genomic landscape and druggable alterations. It also highlighted the role of specific RNF43 frameshift mutations, which unveil the potential of an alternative treatment targeting the Wnt/β-Catenin signalling pathway and could be beneficial, especially to Malaysian CRC patients.
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Affiliation(s)
| | - Nurul-Syakima Ab Mutalib
- UKM Medical Molecular Biology Institute (UMBI), Kuala Lumpur, Malaysia,*Correspondence: Nurul-Syakima Ab Mutalib, ; Rahman Jamal,
| | | | - Sazuita Saidin
- UKM Medical Molecular Biology Institute (UMBI), Kuala Lumpur, Malaysia
| | - Muhiddin Ishak
- UKM Medical Molecular Biology Institute (UMBI), Kuala Lumpur, Malaysia
| | | | | | | | | | | | - Nadiah Abu
- UKM Medical Molecular Biology Institute (UMBI), Kuala Lumpur, Malaysia
| | - Isa Md Rose
- Department of Pathology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - Ismail Sagap
- Department of Surgery, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - Luqman Mazlan
- Department of Surgery, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - Rahman Jamal
- UKM Medical Molecular Biology Institute (UMBI), Kuala Lumpur, Malaysia,*Correspondence: Nurul-Syakima Ab Mutalib, ; Rahman Jamal,
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Li DD, Tang YL, Wang X. Challenges and exploration for immunotherapies targeting cold colorectal cancer. World J Gastrointest Oncol 2023; 15:55-68. [PMID: 36684057 PMCID: PMC9850757 DOI: 10.4251/wjgo.v15.i1.55] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Revised: 10/28/2022] [Accepted: 12/07/2022] [Indexed: 01/10/2023] Open
Abstract
In recent years, immune checkpoint inhibitors (ICIs) have made significant breakthroughs in the treatment of various tumors, greatly improving clinical efficacy. As the fifth most common antitumor treatment strategy for patients with solid tumors after surgery, chemotherapy, radiotherapy and targeted therapy, the therapeutic response to ICIs largely depends on the number and spatial distribution of effector T cells that can effectively identify and kill tumor cells, features that are also important when distinguishing malignant tumors from “cold tumors” or “hot tumors”. At present, only a small proportion of colorectal cancer (CRC) patients with deficient mismatch repair (dMMR) or who are microsatellite instability-high (MSI-H) can benefit from ICI treatments because these patients have the characteristics of a “hot tumor”, with a high tumor mutational burden (TMB) and massive immune cell infiltration, making the tumor more easily recognized by the immune system. In contrast, a majority of CRC patients with proficient MMR (pMMR) or who are microsatellite stable (MSS) have a low TMB, lack immune cell infiltration, and have almost no response to immune monotherapy; thus, these tumors are “cold”. The greatest challenge today is how to improve the immunotherapy response of “cold tumor” patients. With the development of clinical research, immunotherapies combined with other treatment strategies (such as targeted therapy, chemotherapy, and radiotherapy) have now become potentially effective clinical strategies and research hotspots. Therefore, the question of how to promote the transformation of “cold tumors” to “hot tumors” and break through the bottleneck of immunotherapy for cold tumors in CRC patients urgently requires consideration. Only by developing an in-depth understanding of the immunotherapy mechanisms of cold CRCs can we screen out the immunotherapy-dominant groups and explore the most suitable treatment options for individuals to improve therapeutic efficacy.
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Affiliation(s)
- Dan-Dan Li
- Department of Abdominal Oncology/Radiation Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Yuan-Ling Tang
- Department of Abdominal Oncology/Radiation Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Xin Wang
- Department of Abdominal Oncology/Radiation Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
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Klemen ND, Court CM, Fernandes MC, Walch HS, Chatila WK, Saadat LV, Maron S, Crane C, Shia J, Cercek A, Gönen M, Schultz ND, Garcia Aguilar J, Jarnagin WR, D'Angelica MI. Local Therapy for Oligoprogression or Consolidation in High Mutational Burden Stage 4 Colorectal Cancer Treated With PD-1 or PD-L1 Blockade. Ann Surg Oncol 2022; 29:8373-8382. [PMID: 35930112 PMCID: PMC9649851 DOI: 10.1245/s10434-022-12095-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2022] [Accepted: 06/12/2022] [Indexed: 12/13/2022]
Abstract
BACKGROUND Immune checkpoint blockade (ICI) of programmed cell death protein 1 (PD-1) or PD-1 ligand (PD-L1) can induce durable responses in patients who have colorectal cancer (CRC) with a high tumor mutational burden (TMB). Two recurring clinical dilemmas show how to manage oligoprogressive disease and stable disease after ICI. METHODS A cohort study was conducted to analyze patients with metastatic CRC who underwent PD-1 or PD-L1 blockade. Tumors were mismatch repair (MMR) deficient or had more than 25 mutations per megabase. Patients were identified who had local therapy (surgery, ablation, or radiotherapy) for one to three sites of progressive disease (PD) or surgery to consolidate SD. The study evaluated clinical and biologic factors associated with patient selection, outcomes, and pathologic response rates. RESULTS From 2014 to 2020, treatment was administered to 111 patients with ICI. Of these 111 patients, 19 (17%) survived fewer than 6 months, whereas to date, 50 have not had progression of disease. The remaining 42 patients experienced PD, and 16 (38%) were treated with local therapy for oligoprogression. Selection for local therapy was associated with response to ICI. The 2-year progression-free survival (PFS) after local therapy was 62%. Finally, 6 of the 50 patients without PD had consolidation of SD, and 5 had complete or near complete pathologic responses. CONCLUSIONS Oligoprogression, a frequent pattern of failure after ICI, can be managed effectively with local therapy. In contrast, it may not be necessary to consolidate SD for selected patients. Further research is essential to define management algorithms better and to explore heterogeneity in response patterns.
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Affiliation(s)
- Nicholas D Klemen
- Department of Surgery, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA
| | - Colin M Court
- Department of Surgery, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA
| | | | - Henry S Walch
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Walid K Chatila
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Lily V Saadat
- Department of Surgery, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA
| | - Steven Maron
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Chris Crane
- Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Jinru Shia
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Andrea Cercek
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Mithat Gönen
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Nikolaus D Schultz
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Julio Garcia Aguilar
- Department of Surgery, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA
| | - William R Jarnagin
- Department of Surgery, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA
| | - Michael I D'Angelica
- Department of Surgery, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA.
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Borelli B, Antoniotti C, Carullo M, Germani MM, Conca V, Masi G. Immune-Checkpoint Inhibitors (ICIs) in Metastatic Colorectal Cancer (mCRC) Patients beyond Microsatellite Instability. Cancers (Basel) 2022; 14:4974. [PMID: 36291761 PMCID: PMC9599678 DOI: 10.3390/cancers14204974] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2022] [Revised: 10/05/2022] [Accepted: 10/07/2022] [Indexed: 09/06/2023] Open
Abstract
Immune-checkpoint inhibitors (ICIs) showed impressive results in terms of activity and efficacy in metastatic colorectal cancer (mCRC) patients bearing tumors with deficient mismatch repair (dMMR) or high microsatellite instability (MSI-H). Despite that microsatellite status is the major predictive biomarker for the efficacy of ICIs, a proportion of dMMR/MSI-H mCRC tumors do not achieve benefit from immunotherapy due to the primary resistance. Deeper knowledge of biological mechanisms regulating dMMR/MSI-H CRC tumors and immune response may be useful to find new predictive biomarkers of ICIs benefit and tailor the use of immunotherapy even in dMMR/MSI-H mCRC patients. Moreover, several issues are still open, such as the secondary resection of metastases and the optimal duration of ICIs therapy in dMMR/MSI-H mCRC patients. Looking beyond microsatellite status, in a future perspective, several tools (i.e., Tumor Mutational Burden and PD-L1 expression) have been investigated to clarify their possible role as predictive biomarkers. Furthermore, a small subgroup of pMMR/MSS CRC tumors with a POLE mutation of the proofreading domain is characterized by hypermutated phenotype and might derive benefit from immune checkpoint inhibition. In the present work, we aim to review the most recent literature regarding treatment with ICIs in mCRC, focusing on dMMR/MSI-H and special subgroups of CRC patients. Hence, we summarize possible future targets and the most promising predictive biomarkers.
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Affiliation(s)
- Beatrice Borelli
- Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, 56126 Pisa, Italy
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, 56126 Pisa, Italy
| | - Carlotta Antoniotti
- Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, 56126 Pisa, Italy
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, 56126 Pisa, Italy
| | - Martina Carullo
- Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, 56126 Pisa, Italy
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, 56126 Pisa, Italy
| | - Marco Maria Germani
- Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, 56126 Pisa, Italy
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, 56126 Pisa, Italy
| | - Veronica Conca
- Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, 56126 Pisa, Italy
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, 56126 Pisa, Italy
| | - Gianluca Masi
- Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, 56126 Pisa, Italy
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, 56126 Pisa, Italy
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Therapeutic targets and biomarkers of tumor immunotherapy: response versus non-response. Signal Transduct Target Ther 2022; 7:331. [PMID: 36123348 PMCID: PMC9485144 DOI: 10.1038/s41392-022-01136-2] [Citation(s) in RCA: 227] [Impact Index Per Article: 75.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2022] [Revised: 06/25/2022] [Accepted: 07/25/2022] [Indexed: 02/05/2023] Open
Abstract
Cancers are highly complex diseases that are characterized by not only the overgrowth of malignant cells but also an altered immune response. The inhibition and reprogramming of the immune system play critical roles in tumor initiation and progression. Immunotherapy aims to reactivate antitumor immune cells and overcome the immune escape mechanisms of tumors. Represented by immune checkpoint blockade and adoptive cell transfer, tumor immunotherapy has seen tremendous success in the clinic, with the capability to induce long-term regression of some tumors that are refractory to all other treatments. Among them, immune checkpoint blocking therapy, represented by PD-1/PD-L1 inhibitors (nivolumab) and CTLA-4 inhibitors (ipilimumab), has shown encouraging therapeutic effects in the treatment of various malignant tumors, such as non-small cell lung cancer (NSCLC) and melanoma. In addition, with the advent of CAR-T, CAR-M and other novel immunotherapy methods, immunotherapy has entered a new era. At present, evidence indicates that the combination of multiple immunotherapy methods may be one way to improve the therapeutic effect. However, the overall clinical response rate of tumor immunotherapy still needs improvement, which warrants the development of novel therapeutic designs as well as the discovery of biomarkers that can guide the prescription of these agents. Learning from the past success and failure of both clinical and basic research is critical for the rational design of studies in the future. In this article, we describe the efforts to manipulate the immune system against cancer and discuss different targets and cell types that can be exploited to promote the antitumor immune response.
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Shi C, Qin K, Lin A, Jiang A, Cheng Q, Liu Z, Zhang J, Luo P. The role of DNA damage repair (DDR) system in response to immune checkpoint inhibitor (ICI) therapy. J Exp Clin Cancer Res 2022; 41:268. [PMID: 36071479 PMCID: PMC9450390 DOI: 10.1186/s13046-022-02469-0] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2022] [Accepted: 08/18/2022] [Indexed: 11/10/2022] Open
Abstract
As our understanding of the mechanisms of cancer treatment has increased, a growing number of studies demonstrate pathways through which DNA damage repair (DDR) affects the immune system. At the same time, the varied response of patients to immune checkpoint blockade (ICB) therapy has prompted the discovery of various predictive biomarkers and the study of combination therapy. Here, our investigation explores the interactions involved in combination therapy, accompanied by a review that summarizes currently identified and promising predictors of response to immune checkpoint inhibitors (ICIs) that are useful for classifying oncology patients. In addition, this work, which discusses immunogenicity and several components of the tumor immune microenvironment, serves to illustrate the mechanism by which higher response rates and improved efficacy of DDR inhibitors (DDRi) in combination with ICIs are achieved.
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Favre L, Cohen J, Calderaro J, Pécriaux A, Nguyen C, Bourgoin R, Larnaudie L, Dupuy A, Ollier M, Lechapt E, Sloma I, Tournigand C, Rousseau B, Pujals A. High prevalence of unusual KRAS, NRAS, and BRAF mutations in POLE-hypermutated colorectal cancers. Mol Oncol 2022; 16:3055-3065. [PMID: 35624529 PMCID: PMC9441000 DOI: 10.1002/1878-0261.13257] [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: 12/22/2021] [Revised: 04/05/2022] [Accepted: 05/25/2022] [Indexed: 12/04/2022] Open
Abstract
Exonucleasic domain POLE (edPOLE) mutations, which are responsible for a hypermutated tumor phenotype, occur in 1-2% of colorectal cancer (CRC) cases. These alterations represent an emerging biomarker for response to immune checkpoint blockade. This study aimed to assess the molecular characteristics of edPOLE-mutated tumors to facilitate patient screening. Based on opensource data analysis, we compared the prevalence of edPOLE mutations in a control group of unselected CRC patients (n = 222) vs a group enriched for unusual BRAF/RAS mutations (n = 198). Tumor mutational burden (TMB) and immune infiltrate of tumors harboring edPOLE mutations were then analyzed. In total, 420 CRC patients were analyzed: 11 edPOLE-mutated tumors were identified, most frequently in microsatellite (MMR)-proficient young (< 70 years) male patients, with left-sided tumors harboring noncodon 12 KRAS mutation. The prevalence of edPOLE-mutated tumors in the control vs the experimental screening group was, respectively, 0.45% (n = 1) vs 5.0% (n = 10). Among the 11 edPOLE-mutated cases, two had a low TMB, three were hypermutated, and six were ultramutated. EdPOLE-mutated cases had a high CD8+ tumor-infiltrating lymphocyte (TIL) infiltration. These clinicopathological and molecular criteria may help to identify edPOLE mutations associated with a high TMB in CRC, and improve the selection of patients who could benefit from immunotherapy.
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Affiliation(s)
- Loetitia Favre
- Département de PathologieAP‐HP, Centre Hospitalier Universitaire Henri MondorCréteilFrance
- INSERM, IMRBUniv Paris Est CreteilFrance
| | - Justine Cohen
- Département de PathologieAP‐HP, Centre Hospitalier Universitaire Henri MondorCréteilFrance
| | - Julien Calderaro
- Département de PathologieAP‐HP, Centre Hospitalier Universitaire Henri MondorCréteilFrance
- INSERM, IMRBUniv Paris Est CreteilFrance
| | - Adrien Pécriaux
- Département de PathologieAP‐HP, Centre Hospitalier Universitaire Henri MondorCréteilFrance
| | | | - Rémi Bourgoin
- Département de PathologieAP‐HP, Centre Hospitalier Universitaire Henri MondorCréteilFrance
| | - Laura Larnaudie
- Département de PathologieAP‐HP, Centre Hospitalier Universitaire Henri MondorCréteilFrance
| | | | - Marie Ollier
- Département de PathologieAP‐HP, Centre Hospitalier Universitaire Henri MondorCréteilFrance
| | - Emmanuèle Lechapt
- Département de PathologieAP‐HP, Centre Hospitalier Universitaire Henri MondorCréteilFrance
- INSERM, IMRBUniv Paris Est CreteilFrance
| | - Ivan Sloma
- INSERM, IMRBUniv Paris Est CreteilFrance
- Département d'Hématologie BiologiqueAP‐HP, Centre Hospitalier Universitaire Henri MondorCréteilFrance
| | - Christophe Tournigand
- INSERM, IMRBUniv Paris Est CreteilFrance
- Service d'Oncologie MédicaleAP‐HP, Centre Hospitalier Universitaire Henri MondorCréteilFrance
| | - Benoit Rousseau
- Service d'Oncologie MédicaleAP‐HP, Centre Hospitalier Universitaire Henri MondorCréteilFrance
- Mortimer B. Zuckerman Research CenterMemorial Sloan Kettering Cancer CenterNew YorkNYUSA
| | - Anaïs Pujals
- Département de PathologieAP‐HP, Centre Hospitalier Universitaire Henri MondorCréteilFrance
- INSERM, IMRBUniv Paris Est CreteilFrance
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Firnau MB, Brieger A. CK2 and the Hallmarks of Cancer. Biomedicines 2022; 10:1987. [PMID: 36009534 PMCID: PMC9405757 DOI: 10.3390/biomedicines10081987] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2022] [Revised: 08/08/2022] [Accepted: 08/10/2022] [Indexed: 11/29/2022] Open
Abstract
Cancer is a leading cause of death worldwide. Casein kinase 2 (CK2) is commonly dysregulated in cancer, impacting diverse molecular pathways. CK2 is a highly conserved serine/threonine kinase, constitutively active and ubiquitously expressed in eukaryotes. With over 500 known substrates and being estimated to be responsible for up to 10% of the human phosphoproteome, it is of significant importance. A broad spectrum of diverse types of cancer cells has been already shown to rely on disturbed CK2 levels for their survival. The hallmarks of cancer provide a rationale for understanding cancer's common traits. They constitute the maintenance of proliferative signaling, evasion of growth suppressors, resisting cell death, enabling of replicative immortality, induction of angiogenesis, the activation of invasion and metastasis, as well as avoidance of immune destruction and dysregulation of cellular energetics. In this work, we have compiled evidence from the literature suggesting that CK2 modulates all hallmarks of cancer, thereby promoting oncogenesis and operating as a cancer driver by creating a cellular environment favorable to neoplasia.
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Affiliation(s)
| | - Angela Brieger
- Department of Internal Medicine I, Biomedical Research Laboratory, University Hospital Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany
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Barbari SR, Beach AK, Markgren JG, Parkash V, Moore E, Johansson E, Shcherbakova PV. Enhanced polymerase activity permits efficient synthesis by cancer-associated DNA polymerase ϵ variants at low dNTP levels. Nucleic Acids Res 2022; 50:8023-8040. [PMID: 35822874 PMCID: PMC9371911 DOI: 10.1093/nar/gkac602] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2022] [Revised: 06/13/2022] [Accepted: 06/29/2022] [Indexed: 11/28/2022] Open
Abstract
Amino acid substitutions in the exonuclease domain of DNA polymerase ϵ (Polϵ) cause ultramutated tumors. Studies in model organisms suggested pathogenic mechanisms distinct from a simple loss of exonuclease. These mechanisms remain unclear for most recurrent Polϵ mutations. Particularly, the highly prevalent V411L variant remained a long-standing puzzle with no detectable mutator effect in yeast despite the unequivocal association with ultramutation in cancers. Using purified four-subunit yeast Polϵ, we assessed the consequences of substitutions mimicking human V411L, S459F, F367S, L424V and D275V. While the effects on exonuclease activity vary widely, all common cancer-associated variants have increased DNA polymerase activity. Notably, the analog of Polϵ-V411L is among the strongest polymerases, and structural analysis suggests defective polymerase-to-exonuclease site switching. We further show that the V411L analog produces a robust mutator phenotype in strains that lack mismatch repair, indicating a high rate of replication errors. Lastly, unlike wild-type and exonuclease-dead Polϵ, hyperactive variants efficiently synthesize DNA at low dNTP concentrations. We propose that this characteristic could promote cancer cell survival and preferential participation of mutator polymerases in replication during metabolic stress. Our results support the notion that polymerase fitness, rather than low fidelity alone, is an important determinant of variant pathogenicity.
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Affiliation(s)
- Stephanie R Barbari
- Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Annette K Beach
- Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Joel G Markgren
- Department of Medical Biochemistry and Biophysics, Umeå University, SE-90187 Umeå, Sweden
| | - Vimal Parkash
- Department of Medical Biochemistry and Biophysics, Umeå University, SE-90187 Umeå, Sweden
| | - Elizabeth A Moore
- Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Erik Johansson
- Department of Medical Biochemistry and Biophysics, Umeå University, SE-90187 Umeå, Sweden
| | - Polina V Shcherbakova
- Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA
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Weng J, Li S, Zhu Z, Liu Q, Zhang R, Yang Y, Li X. Exploring immunotherapy in colorectal cancer. J Hematol Oncol 2022; 15:95. [PMID: 35842707 PMCID: PMC9288068 DOI: 10.1186/s13045-022-01294-4] [Citation(s) in RCA: 179] [Impact Index Per Article: 59.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2022] [Accepted: 05/18/2022] [Indexed: 02/07/2023] Open
Abstract
Chemotherapy combined with or without targeted therapy is the fundamental treatment for metastatic colorectal cancer (mCRC). Due to the adverse effects of chemotherapeutic drugs and the biological characteristics of the tumor cells, it is difficult to make breakthroughs in traditional strategies. The immune checkpoint blockades (ICB) therapy has made significant progress in the treatment of advanced malignant tumors, and patients who benefit from this therapy may obtain a long-lasting response. Unfortunately, immunotherapy is only effective in a limited number of patients with microsatellite instability-high (MSI-H), and segment initial responders can subsequently develop acquired resistance. From September 4, 2014, the first anti-PD-1/PD-L1 drug Pembrolizumab was approved by the FDA for the second-line treatment of advanced malignant melanoma. Subsequently, it was approved for mCRC second-line treatment in 2017. Immunotherapy has rapidly developed in the past 7 years. The in-depth research of the ICB treatment indicated that the mechanism of colorectal cancer immune-resistance has become gradually clear, and new predictive biomarkers are constantly emerging. Clinical trials examining the effect of immune checkpoints are actively carried out, in order to produce long-lasting effects for mCRC patients. This review summarizes the treatment strategies for mCRC patients, discusses the mechanism and application of ICB in mCRC treatment, outlines the potential markers of the ICB efficacy, lists the key results of the clinical trials, and collects the recent basic research results, in order to provide a theoretical basis and practical direction for immunotherapy strategies.
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Affiliation(s)
- Junyong Weng
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, 270 Dong'an Road, Xuhui, Shanghai, 200032, China
| | - Shanbao Li
- Department of General Surgery, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200080, China
| | - Zhonglin Zhu
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, 270 Dong'an Road, Xuhui, Shanghai, 200032, China
| | - Qi Liu
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, 270 Dong'an Road, Xuhui, Shanghai, 200032, China
| | - Ruoxin Zhang
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, 270 Dong'an Road, Xuhui, Shanghai, 200032, China
| | - Yufei Yang
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, 270 Dong'an Road, Xuhui, Shanghai, 200032, China
| | - Xinxiang Li
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, 270 Dong'an Road, Xuhui, Shanghai, 200032, China.
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Randrian V, Pernot S, Le Malicot K, Catena V, Baumgaertner I, Tacher V, Forestier J, Hautefeuille V, Tabouret-Viaud C, Gagnaire A, Mitry E, Guiu B, Aparicio T, Smith D, Dhomps A, Tasu JP, Perdrisot R, Edeline J, Capron C, Cheze-Le Rest C, Emile JF, Laurent-Puig P, Bejan-Angoulvant T, Sokol H, Lepage C, Taieb J, Tougeron D. FFCD 1709-SIRTCI phase II trial: Selective internal radiation therapy plus Xelox, Bevacizumab and Atezolizumab in liver-dominant metastatic colorectal cancer. Dig Liver Dis 2022; 54:857-863. [PMID: 35610167 DOI: 10.1016/j.dld.2022.04.024] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2022] [Revised: 04/09/2022] [Accepted: 04/22/2022] [Indexed: 12/24/2022]
Abstract
Immune checkpoint inhibitors (ICI) have high efficacy in metastatic colorectal cancer (mCRC) with microsatellite instability (MSI) but not in microsatellite stable (MSS) tumour due to the low tumour mutational burden. Selective internal radiation therapy (SIRT) could enhance neoantigen production thus triggering systemic anti-tumoral immune response (abscopal effect). In addition, Oxalipatin can induce immunogenic cell death and Bevacizumab can decrease the exhaustion of tumour infiltrating lymphocyte. In combination, these treatments could act synergistically to sensitize MSS mCRCs to ICI SIRTCI is a prospective, multicentre, open-label, phase II, non-comparative single-arm study evaluating the efficacy and safety of SIRT plus Xelox, Bevacizumab and Atezolizumab (anti-programmed death-ligand 1) in patients with liver-dominant MSS mCRC. The primary objective is progression-free survival at 9 months. The main inclusion criteria are patients with MSS mCRC with liver-dominant disease, initially unresectable disease and with no prior oncologic treatment for metastatic disease. The trial started in November 2020 and has included 10 out of the 52 planned patients.
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Affiliation(s)
- Violaine Randrian
- Service d'Hépato-gastroentérologie, CHU de Poitiers et Université de Poitiers, Poitiers 86021, France
| | - Simon Pernot
- Department of Medical Oncology, Institut Bergonié, Bordeaux, France
| | - Karine Le Malicot
- Fédération Francophone de Cancérologie Digestive, EPICAD INSERM LNC-UMR 1231, University of Burgundy and Franche Comté, Dijon, France
| | - Vittorio Catena
- Department of Radiology, Institut Bergonié, Bordeaux, France
| | | | - Vania Tacher
- University of Paris Est Créteil, Unité INSERM 955, Equipe 18, AP-HP, Hôpitaux Universitaires Henri Mondor, Créteil F-94010, France
| | - Julien Forestier
- Department of Medical Oncology, Hôpital Edouard Herriot, Lyon Cedex 03 69437, France
| | - Vincent Hautefeuille
- Department of Hepato-Gastroenterology and Digestive Oncology, Amiens University Hospital, Amiens, France
| | - Claire Tabouret-Viaud
- Department of Nuclear Medicine, Unicancer-Georges François Leclerc Cancer Center, Dijon, France
| | - Alice Gagnaire
- Department of Hepato-Gastroenterology and Digestive Oncology, Dijon University Hospital, BP 87900 21079 Dijon, EPICAD LNC-UMR1231, Burgundy and Franche-Comte University, Dijon, France
| | - Emmanuel Mitry
- Medical Oncology Department, Paoli-Calmettes Institut, Marseille, France
| | - Boris Guiu
- Hôpital St-Eloi (CHU Montpellier), Université de Montpellier, Montpellier, France
| | - Thomas Aparicio
- AP-HP, Gastroenterology and Digestive Oncology Department, Saint Louis Hospital, 1 avenue Claude Vellefaux, Université de Paris, Paris F-75010, France
| | - Denis Smith
- Service d'Oncologie médicale, Haut-Lévèque Hospital, CHU Bordeaux, Bordeaux, France
| | - Anthony Dhomps
- Nuclear Medicine, University Hospital of Lyon, Pierre Bénite, France
| | - Jean-Pierre Tasu
- Radiology Department, University Hospital Centre Poitiers, Poitiers, France; LATIM, INSERM UMR 1101, Université de Brest, CHU Morvan, 2 avenue FOCH, 29 609 Brest cedex, France
| | - Rémy Perdrisot
- Nuclear Medicine, Poitiers University Hospital, Poitiers France
| | - Julien Edeline
- Medical Oncology, Centre Eugène Marquis, Rennes 35000, France
| | - Claude Capron
- Service d'immunologie, AP-HP, Hôpital Ambroise Paré, Paris, France
| | - Catherine Cheze-Le Rest
- LATIM, INSERM UMR 1101, Université de Brest, CHU Morvan, 2 avenue FOCH, 29 609 Brest cedex, France; Nuclear Medicine, Poitiers University Hospital, Poitiers France
| | - Jean-François Emile
- Department of Pathology, APHP-Hôpital Ambroise Paré, Boulogne-Billancourt, France
| | - Pierre Laurent-Puig
- Department of Biology, Georges Pompidou Hospital, APHP, Université de Paris, Paris, France
| | | | - Harry Sokol
- Sorbonne Université, INSERM UMRS-938, Centre de Recherche Saint-Antoine, CRSA, AP-HP, Hôpital Saint-Antoine, Service de Gastroentérologie, Paris, Université Paris-Saclay, INRAE, AgroParisTech, Micalis Institute, Jouy-en-Josas and Center for Microbiome Medicine (PaCeMM) FHU, Paris, France
| | - Come Lepage
- Department of Hepato-Gastroenterology and Digestive Oncology, Dijon University Hospital, BP 87900 21079 Dijon, EPICAD LNC-UMR1231, Burgundy and Franche-Comte University, Dijon, France
| | - Julien Taieb
- Service de Gastroentérologie et d'Oncologie Digestive, Hôpital Européen George Pompidou, Université de Paris, AP-HP, Paris, France
| | - David Tougeron
- Service d'Hépato-gastroentérologie, CHU de Poitiers et Université de Poitiers, Poitiers 86021, France.
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Della Chiesa M, Setti C, Giordano C, Obino V, Greppi M, Pesce S, Marcenaro E, Rutigliani M, Provinciali N, Paleari L, DeCensi A, Sivori S, Carlomagno S. NK Cell-Based Immunotherapy in Colorectal Cancer. Vaccines (Basel) 2022; 10:1033. [PMID: 35891197 PMCID: PMC9323201 DOI: 10.3390/vaccines10071033] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Revised: 06/22/2022] [Accepted: 06/25/2022] [Indexed: 02/01/2023] Open
Abstract
Human Natural Killer (NK) cells are all round players in immunity thanks to their powerful and immediate response against transformed cells and the ability to modulate the subsequent adaptive immune response. The potential of immunotherapies based on NK cell involvement has been initially revealed in the hematological setting but has inspired the design of different immune tools to also be applied against solid tumors, including colorectal cancer (CRC). Indeed, despite cancer prevention screening plans, surgery, and chemotherapy strategies, CRC is one of the most widespread cancers and with the highest mortality rate. Therefore, further efficient and complementary immune-based therapies are in urgent need. In this review, we gathered the most recent advances in NK cell-based immunotherapies aimed at fighting CRC, in particular, the use of monoclonal antibodies targeting tumor-associated antigens (TAAs), immune checkpoint blockade, and adoptive NK cell therapy, including NK cells modified with chimeric antigen receptor (CAR-NK).
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Affiliation(s)
- Mariella Della Chiesa
- Department of Experimental Medicine (DIMES), University of Genoa, 16132 Genoa, Italy; (C.S.); (C.G.); (V.O.); (M.G.); (S.P.); (E.M.); (S.S.)
| | - Chiara Setti
- Department of Experimental Medicine (DIMES), University of Genoa, 16132 Genoa, Italy; (C.S.); (C.G.); (V.O.); (M.G.); (S.P.); (E.M.); (S.S.)
| | - Chiara Giordano
- Department of Experimental Medicine (DIMES), University of Genoa, 16132 Genoa, Italy; (C.S.); (C.G.); (V.O.); (M.G.); (S.P.); (E.M.); (S.S.)
| | - Valentina Obino
- Department of Experimental Medicine (DIMES), University of Genoa, 16132 Genoa, Italy; (C.S.); (C.G.); (V.O.); (M.G.); (S.P.); (E.M.); (S.S.)
| | - Marco Greppi
- Department of Experimental Medicine (DIMES), University of Genoa, 16132 Genoa, Italy; (C.S.); (C.G.); (V.O.); (M.G.); (S.P.); (E.M.); (S.S.)
| | - Silvia Pesce
- Department of Experimental Medicine (DIMES), University of Genoa, 16132 Genoa, Italy; (C.S.); (C.G.); (V.O.); (M.G.); (S.P.); (E.M.); (S.S.)
| | - Emanuela Marcenaro
- Department of Experimental Medicine (DIMES), University of Genoa, 16132 Genoa, Italy; (C.S.); (C.G.); (V.O.); (M.G.); (S.P.); (E.M.); (S.S.)
| | | | | | - Laura Paleari
- A.Li.Sa., Liguria Region Health Authority, 16121 Genoa, Italy;
| | - Andrea DeCensi
- Medical Oncology, Galliera Hospital, 16128 Genoa, Italy; (N.P.); (A.D.)
| | - Simona Sivori
- Department of Experimental Medicine (DIMES), University of Genoa, 16132 Genoa, Italy; (C.S.); (C.G.); (V.O.); (M.G.); (S.P.); (E.M.); (S.S.)
| | - Simona Carlomagno
- Department of Experimental Medicine (DIMES), University of Genoa, 16132 Genoa, Italy; (C.S.); (C.G.); (V.O.); (M.G.); (S.P.); (E.M.); (S.S.)
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Kumar S U, Balasundaram A, Cathryn R H, Varghese RP, R S, R G, Younes S, Zayed H, Doss C GP. Whole-exome sequencing analysis of NSCLC reveals the pathogenic missense variants from cancer-associated genes. Comput Biol Med 2022; 148:105701. [PMID: 35753820 DOI: 10.1016/j.compbiomed.2022.105701] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Revised: 05/17/2022] [Accepted: 06/04/2022] [Indexed: 11/16/2022]
Abstract
BACKGROUND Non-small-cell lung cancer (NSCLC) is the most common type of lung cancer. NSCLC accounts for 84% of all lung cancer cases. In recent years, advances in pathway understanding, methods for discovering novel genetic biomarkers, and new drugs designed to inhibit the signaling cascades have enabled clinicians to personalize therapy for NSCLC. OBJECTIVES The primary aim of this study is to identify the genes associated with NSCLC that harbor pathogenic variants that could be causative for NSCLC. The second aim is to investigate their roles in different pathways that lead to NSCLC. METHODS We examined exome-sequencing datasets from 54 NSCLC patients to characterize the variants associated with NSCLC. RESULTS Our findings revealed that 17 variants in 14 genes were considered highly pathogenic, including CDKN2A, ERBB2, FOXP1, IDH1, JAK3, KMT2D, K-Ras, MSH3, MSH6, POLE, RNF43, TCF7L2, TP53, and TSC1. Gene set enrichment analysis revealed the involvement of transmembrane receptor protein tyrosine kinase activity, protein binding, ATP binding, phosphatidylinositol-4,5-bisphosphate 3-kinase, and Ras guanyl-nucleotide exchange factor activity. Pathway analysis of these genes yielded different cancer-related pathways, including colorectal, prostate, endometrial, pancreatic, PI3K-Akt signaling pathways, and signaling pathways regulating pluripotency of stem cells. Module 1 from protein-protein interactions (PPIs) identified genes that harbor pathogenic SNPs. Three of the most deleterious SNPs are ERBB2 (rs1196929947), K-Ras (rs121913529), and POLE (rs751425952). Interestingly, one patient has a pathogenic K-Ras variant (rs121913529) co-occurred with the missense variant (rs752054698) inTSC1 gene. CONCLUSION This study maps highly pathogenic variants associated with NSCLC and investigates their contributions to the pathogenesis of NSCLC. This study sheds light on the potential applications of precision medicine in patients with NSCLC.
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Affiliation(s)
- Udhaya Kumar S
- Laboratory of Integrative Genomics, Department of Integrative Biology, School of Biosciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, 632014, India
| | - Ambritha Balasundaram
- Laboratory of Integrative Genomics, Department of Integrative Biology, School of Biosciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, 632014, India
| | - Hephzibah Cathryn R
- Laboratory of Integrative Genomics, Department of Integrative Biology, School of Biosciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, 632014, India
| | - Rinku Polachirakkal Varghese
- Laboratory of Integrative Genomics, Department of Integrative Biology, School of Biosciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, 632014, India
| | - Siva R
- Laboratory of Integrative Genomics, Department of Integrative Biology, School of Biosciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, 632014, India
| | - Gnanasambandan R
- Laboratory of Integrative Genomics, Department of Integrative Biology, School of Biosciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, 632014, India
| | - Salma Younes
- Department of Biomedical Sciences, College of Health and Sciences, Qatar University, QU Health, Doha, 2713, Qatar
| | - Hatem Zayed
- Department of Biomedical Sciences, College of Health and Sciences, Qatar University, QU Health, Doha, 2713, Qatar
| | - George Priya Doss C
- Laboratory of Integrative Genomics, Department of Integrative Biology, School of Biosciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, 632014, India.
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Sahin IH, Ciombor KK, Diaz LA, Yu J, Kim R. Immunotherapy for Microsatellite Stable Colorectal Cancers: Challenges and Novel Therapeutic Avenues. Am Soc Clin Oncol Educ Book 2022; 42:1-12. [PMID: 35658496 DOI: 10.1200/edbk_349811] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
With the development of immune checkpoint inhibitors, immunotherapy researchers have facilitated substantial progress for patients with mismatch repair deficient/microsatellite instability-high colorectal cancer, which has led to practice changes at a head-spinning pace. However, this benefit has not been translated into microsatellite stable colorectal cancer, which carries the hallmarks of chromosomal instability. So far, clinical trials have not shown any substantial clinical benefits of immune checkpoint inhibitor therapy for patients with microsatellite stable colorectal cancer, which has been disappointing. Recently, combinations of immune checkpoint inhibitors with tyrosine kinase inhibitors and targeted therapies have been investigated for potential synergistic effects that may increase antitumor activity in the tumor microenvironment and achieve more substantial clinical and radiologic responses. In this article, we discuss the current state of the science for the use of immune checkpoint inhibitors in microsatellite stable colorectal cancers, and we review the molecular underpinnings of inherited physiologic barriers for the delivery of effective immunotherapy. We also elaborate on existing therapeutic opportunities to convert microsatellite stable colorectal cancer into an "immune hot" cancer, which may define the future treatment paradigm of colorectal cancer for which there is a great unmet need.
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Affiliation(s)
| | | | - Luis A Diaz
- Memorial Sloan Kettering Cancer Center, New York, NY
| | | | - Richard Kim
- H. Lee Moffitt Cancer Center and Research Institute, Tampa FL
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Cui G. Towards a precision immune checkpoint blockade immunotherapy in patients with colorectal cancer: Strategies and perspectives. Biomed Pharmacother 2022; 149:112923. [PMID: 36068782 DOI: 10.1016/j.biopha.2022.112923] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2022] [Revised: 03/29/2022] [Accepted: 04/04/2022] [Indexed: 11/02/2022] Open
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Ulreich K, Firnau MB, Tagscherer N, Beyer S, Ackermann A, Plotz G, Brieger A. High Expression of Casein Kinase 2 Alpha Is Responsible for Enhanced Phosphorylation of DNA Mismatch Repair Protein MLH1 and Increased Tumor Mutation Rates in Colorectal Cancer. Cancers (Basel) 2022; 14:cancers14061553. [PMID: 35326704 PMCID: PMC8946085 DOI: 10.3390/cancers14061553] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2022] [Revised: 03/10/2022] [Accepted: 03/15/2022] [Indexed: 02/05/2023] Open
Abstract
Simple Summary Colorectal cancer (CRC) is associated with DNA mismatch repair (MMR) deficiency. The serine/threonine casein kinase 2 alpha (CK2α) is able to phosphorylate and inhibit MMR protein MLH1 in vitro. This study aimed to analyze the relevance of CK2α for MLH1 phosphorylation in vivo. Around 50% of CRCs were identified to express significantly increased nuclear/cytoplasmic CK2α. High nuclear/cytoplasmic CK2α level could be significantly correlated with reduced 5-year survival outcome of patients, increased MLH1 phosphorylation, and enriched somatic tumor mutation rates. Overall, our study demonstrated, in vivo, that enhanced CK2α leads to an increase of MLH1 phosphorylation, higher tumor mutation rates, and is an unfavorable prognosis for patients. Abstract DNA mismatch repair (MMR) deficiency plays an essential role in the development of colorectal cancer (CRC). We recently demonstrated in vitro that the serine/threonine casein kinase 2 alpha (CK2α) causes phosphorylation of the MMR protein MLH1 at position serine 477, which significantly inhibits the MMR. In the present study, CK2α-dependent MLH1 phosphorylation was analyzed in vivo. Using a cohort of 165 patients, we identified 88 CRCs showing significantly increased nuclear/cytoplasmic CK2α expression, 28 tumors with high nuclear CK2α expression and 49 cases showing a general low CK2α expression. Patients with high nuclear/cytoplasmic CK2α expression demonstrated significantly reduced 5-year survival outcome. By immunoprecipitation and Western blot analysis, we showed that high nuclear/cytoplasmic CK2α expression significantly correlates with increased MLH1 phosphorylation and enriched somatic tumor mutation rates. The CK2α mRNA levels tended to be enhanced in high nuclear/cytoplasmic and high nuclear CK2α-expressing tumors. Furthermore, we identified various SNPs in the promotor region of CK2α, which might cause differential CK2α expression. In summary, we demonstrated that high nuclear/cytoplasmic CK2α expression in CRCs correlates with enhanced MLH1 phosphorylation in vivo and seems to be causative for increased mutation rates, presumably induced by reduced MMR. These observations could provide important new therapeutic targets.
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Polymerase Epsilon-Associated Ultramutagenesis in Cancer. Cancers (Basel) 2022; 14:cancers14061467. [PMID: 35326618 PMCID: PMC8946778 DOI: 10.3390/cancers14061467] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Revised: 03/09/2022] [Accepted: 03/09/2022] [Indexed: 01/27/2023] Open
Abstract
With advances in next generation sequencing (NGS) technologies, efforts have been made to develop personalized medicine, targeting the specific genetic makeup of an individual. Somatic or germline DNA Polymerase epsilon (PolE) mutations cause ultramutated (>100 mutations/Mb) cancer. In contrast to mismatch repair-deficient hypermutated (>10 mutations/Mb) cancer, PolE-associated cancer is primarily microsatellite stable (MSS) In this article, we provide a comprehensive review of this PolE-associated ultramutated tumor. We describe its molecular characteristics, including the mutation sites and mutation signature of this type of tumor and the mechanism of its ultramutagenesis. We discuss its good clinical prognosis and elucidate the mechanism for enhanced immunogenicity with a high tumor mutation burden, increased neoantigen load, and enriched tumor-infiltrating lymphocytes. We also provide the rationale for immune checkpoint inhibitors in PolE-mutated tumors.
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Durando ML, Menghani SV, Baumann JL, Robles DG, Day TA, Vaziri C, Scott AJ. Four-Year Disease-Free Remission in a Patient With POLE Mutation-Associated Colorectal Cancer Treated Using Anti-PD-1 Therapy. J Natl Compr Canc Netw 2022; 20:218-223. [PMID: 35276675 DOI: 10.6004/jnccn.2021.7115] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2021] [Accepted: 11/18/2021] [Indexed: 11/17/2022]
Abstract
The stability of the human genome depends upon a delicate balance between replication by high- and low-fidelity DNA polymerases. Aberrant replication by error-prone polymerases or loss of function of high-fidelity polymerases predisposes to genetic instability and, in turn, cancer. DNA polymerase epsilon (Pol ε) is a high-fidelity, processive polymerase that is responsible for the majority of leading strand synthesis, and mutations in Pol ε have been increasingly associated with various human malignancies. The clinical significance of Pol ε mutations, including how and whether they should influence management decisions, remains poorly understood. In this report, we describe a 24-year-old man with an aggressive stage IV high-grade, poorly differentiated colon carcinoma who experienced a dramatic response to single-agent checkpoint inhibitor immunotherapy after rapidly progressing on standard chemotherapy. His response was complete and durable and has been maintained for more than 48 months. Genetic testing revealed a P286R mutation in the endonuclease domain of POLE and an elevated tumor mutational burden of 126 mutations per megabase, both of which have been previously associated with response to immunotherapy. Interestingly, tumor staining for PD-L1 was negative. This case study highlights the importance of genetic profiling of both early and late-stage cancers, the clinical significance of POLE mutations, and how the interplay between genetic instability and immune-checkpoint blockade can impact clinical decision-making.
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Affiliation(s)
- Michael L Durando
- 1Banner-University Medical Center Tucson, Tucson, Arizona.,2Division of Hematology and Oncology, Department of Medicine.,3University of Arizona Cancer Center
| | | | - Jessica L Baumann
- 5Department of Pathology, University of Arizona College of Medicine-Tucson, Tucson, Arizona.,6Now with Roche Tissue Diagnostics, Tucson, Arizona
| | - Danny G Robles
- 1Banner-University Medical Center Tucson, Tucson, Arizona.,7Department of Surgery, University of Arizona College of Medicine-Tucson, Tucson, Arizona
| | - Tovah A Day
- 8Department of Biology, Northeastern University, Boston, Massachusetts; and
| | - Cyrus Vaziri
- 9Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, North Carolina
| | - Aaron J Scott
- 1Banner-University Medical Center Tucson, Tucson, Arizona.,2Division of Hematology and Oncology, Department of Medicine.,3University of Arizona Cancer Center
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Berrino E, Filippi R, Visintin C, Peirone S, Fenocchio E, Farinea G, Veglio F, Aglietta M, Sapino A, Cereda M, Visintin R, Pasini B, Marchiò C. Collision of germline POLE and PMS2 variants in a young patient treated with immune checkpoint inhibitors. NPJ Precis Oncol 2022; 6:15. [PMID: 35260767 PMCID: PMC8904527 DOI: 10.1038/s41698-022-00258-8] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2021] [Accepted: 02/11/2022] [Indexed: 12/30/2022] Open
Abstract
The onset of multiple and metachronous tumors in young patients induces to suspect the presence of genetic variants in genes associated with tumorigenesis. We describe here the unusual case of a 16-year-old patient who developed a synchronous bifocal colorectal adenocarcinoma with distant metastases. We provide high throughput molecular characterization with whole-exome sequencing (WES) and DNA targeted sequencing of different tumoral lesions and normal tissue samples that led to unveil a germline POLE mutation (p.Ser297Cys) coexisting with the PMS2 c.2174 + 1 G > A splicing mutation. This clinical scenario defines a “POLE-LYNCH” collision syndrome, which explains the ultra-mutator phenotype observed in the tumor lesions, and the presence of MMR deficiency-associated unusual signatures. The patient was successfully treated with immune checkpoint inhibitors but subsequently developed a high-grade urothelial carcinoma cured by surgery. We complement this analysis with a transcriptomic characterization of tumoral lesions with a panel targeting 770 genes related to the tumor microenvironment and immune evasion thus getting insight on cancer progression and response to immunotherapy.
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Affiliation(s)
- Enrico Berrino
- Candiolo Cancer Institute, FPO IRCCS, Candiolo, Italy.,Department of Medical Sciences, University of Turin, Turin, Italy
| | - Roberto Filippi
- Department of Oncology, University of Turin, Turin, Italy.,Medical Oncology Unit, University Hospital AOU Città della Salute e della Scienza, Turin, Italy
| | - Clara Visintin
- Department of Experimental Oncology, European Institute of Oncology, IEO IRCCS, Milano, Italy
| | - Serena Peirone
- Candiolo Cancer Institute, FPO IRCCS, Candiolo, Italy.,Cancer Genomics and Bioinformatics Unit, IIGM-Italian Institute for Genomic Medicine, c/o IRCCS Candiolo, 10060, Turin, Italy
| | | | | | - Franco Veglio
- Department of Medical Sciences, University of Turin, Turin, Italy.,Internal Medicine Unit, University Hospital AOU Città della Salute e della Scienza, Turin, Italy
| | - Massimo Aglietta
- Candiolo Cancer Institute, FPO IRCCS, Candiolo, Italy.,Department of Oncology, University of Turin, Turin, Italy
| | - Anna Sapino
- Candiolo Cancer Institute, FPO IRCCS, Candiolo, Italy.,Department of Medical Sciences, University of Turin, Turin, Italy
| | - Matteo Cereda
- Candiolo Cancer Institute, FPO IRCCS, Candiolo, Italy.,Cancer Genomics and Bioinformatics Unit, IIGM-Italian Institute for Genomic Medicine, c/o IRCCS Candiolo, 10060, Turin, Italy
| | - Rosella Visintin
- Department of Experimental Oncology, European Institute of Oncology, IEO IRCCS, Milano, Italy
| | - Barbara Pasini
- Department of Medical Sciences, University of Turin, Turin, Italy. .,Medical Genetics Unit, University Hospital AOU Città della Salute e della Scienza, Turin, Italy.
| | - Caterina Marchiò
- Candiolo Cancer Institute, FPO IRCCS, Candiolo, Italy. .,Department of Medical Sciences, University of Turin, Turin, Italy.
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