|
1
|
Inderberg EM, Singh N, Miller R, Arbe-Barnes S, Eriksen HK, Lversen B, Juul HV, Eriksen JA, Handeland KR. Generation of frameshift-mutated TGFβR2-specific T cells in healthy subjects following administration with cancer vaccine candidate FMPV-1/GM-CSF in a phase 1 study. Cancer Immunol Immunother 2025; 74:115. [PMID: 39998682 PMCID: PMC11861775 DOI: 10.1007/s00262-025-03969-6] [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: 11/08/2024] [Accepted: 02/03/2025] [Indexed: 02/27/2025]
Abstract
FMPV-1 is a component of FMPV-3, an investigational cancer-specific vaccine and being developed to activate anti-cancer T cell responses targeting frameshift mutations of MSI-H cancers. FMPV-1 is designed to activate T cell responses against transforming growth factor β receptor 2 (TGFβR2) frameshift mutation. Microsatellite instability high (MSI-H) gastrointestinal cancers frequently harbour TGFβR2 frameshift mutations. This first-in-human, phase 1, single centre, open-label study included 16 healthy male subjects who received FMPV-1 (0.15 mg/injection) plus granulocyte-macrophage colony-stimulating factor (GM-CSF) (0.03 mg/injection) as two separate, co-located, injections on Days 1, 8, 15, 29 and 43. All subjects were followed to Day 365. A FMPV-1-specific delayed type hypersensitivity (DTH) skin reactivity test was performed with FMPV-1 (without GM-CSF) on Days 1, 29 and 43 with assessment after 2 days. All subjects were DTH negative at baseline, 8/16 were positive on Day 31 and 15/16 were positive on Day 45. Furthermore, the FMPV-1/GM-CSF induced frameshift mutant TGFβR2-specific T cells after the short vaccination period, and specific T cells were still detectable after 6 and 12 months indicating induction of frameshift mutant TGFβR2-specific T memory cells. Adverse events were limited to mild injection site reactions with no evidence of related systemic signs or symptoms. No other clinically important changes to vital signs, electrocardiograms, haematological, coagulation or laboratory measures related to treatment were observed. FMPV-1/GM-CSF was well tolerated and generated vaccine-specific T cell immune responses in healthy subjects. These findings support clinical studies in patients with, or at risk of, cancers carrying TGFβR2 frameshift mutations.Clinical trial identification: ClinicalTrials.gov: NCT05238558. EudraCT: 2020-004363-80.
Collapse
Affiliation(s)
- Else Marit Inderberg
- Translational Research Unit, Section for Cellular Therapy, Department of Oncology, Oslo University Hospital - Radiumhospitalet, Oslo, Norway
| | - Nand Singh
- Medical Department, Quotient Sciences, Nottingham, UK
| | | | | | | | | | - Hedvig Vidarsdotter Juul
- Translational Research Unit, Section for Cellular Therapy, Department of Oncology, Oslo University Hospital - Radiumhospitalet, Oslo, Norway
| | | | | |
Collapse
|
|
2
|
Graciotti M, Kandalaft LE. Vaccines for cancer prevention: exploring opportunities and navigating challenges. Nat Rev Drug Discov 2025; 24:134-150. [PMID: 39622986 DOI: 10.1038/s41573-024-01081-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/24/2024] [Indexed: 02/06/2025]
Abstract
Improved understanding of cancer immunology has gradually brought increasing attention towards cancer-preventive vaccines as an important tool in the fight against cancer. The aim of this approach is to reduce cancer occurrence by inducing a specific immune response targeting tumours at an early stage before they can fully develop. The great advantage of preventive cancer vaccines lies in the potential to harness a less-compromised immune system in vaccine recipients before their immune responses become affected by the advanced status of the disease itself or by aggressive treatments such as chemotherapy. Successful implementation of immunoprevention against oncogenic viruses such as hepatitis B and papillomavirus has led to a dramatic decrease in virally induced cancers. Extending this approach to other cancers holds great promise but remains a major challenge. Here, we provide a comprehensive review of preclinical evidence supporting this approach, encouraging results from pioneering clinical studies as well as a discussion on the key aspects and open questions to address in order to design potent prophylactic cancer vaccines in the near future.
Collapse
Affiliation(s)
- Michele Graciotti
- Center of Experimental Therapeutics, Department of Oncology, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland
- Ludwig Institute for Cancer Research, Lausanne Branch, Lausanne, Switzerland
| | - Lana E Kandalaft
- Ludwig Institute for Cancer Research, Lausanne Branch, Lausanne, Switzerland.
- Department of Oncology, University of Lausanne (UNIL), Lausanne, Switzerland.
- AGORA Cancer Research Center, Lausanne, Lausanne, Switzerland.
- Swiss Medical Network, Genolier Innovation Network, Genolier Clinic, Genolier, Switzerland.
| |
Collapse
|
|
3
|
Elbehi AM. The challenges and opportunities of applying tumour mutational burden analysis to precision cancer medicine. CAMBRIDGE PRISMS. PRECISION MEDICINE 2024; 3:e3. [PMID: 40308330 PMCID: PMC12041339 DOI: 10.1017/pcm.2024.6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 03/24/2023] [Revised: 09/30/2024] [Accepted: 10/22/2024] [Indexed: 05/02/2025]
Abstract
The discovery and development of immune checkpoint inhibitors (ICIs) has revolutionised the management of human cancers. However, only a subset of patients responds to ICI therapy, even though immune evasion is a hallmark of cancer. Initially, treatment was administered to patients on the basis of expression levels of one of the targets of ICI therapy, programmed cell death ligand 1. In clinical trials, the high response rate of melanoma and non-small cell lung cancer patients to ICI therapy supported the basic premise of cancer immunotherapy, that tumour-specific mutated proteins trigger an immune response. Tumour mutational burden subsequently emerged as a potential biomarker for response to ICI therapy. This review summarises the evidence supporting the scientific rationale for TMB as a biomarker for ICI therapy and focuses on some of the major challenges associated with incorporation of TMB into routine clinical practice.
Collapse
Affiliation(s)
- Attia M. Elbehi
- Department of Oncology, Medical Sciences Division, University of Oxford, Oxford, UK
| |
Collapse
|
|
4
|
Martin S, Katainen R, Taira A, Välimäki N, Ristimäki A, Seppälä T, Renkonen-Sinisalo L, Lepistö A, Tahkola K, Mattila A, Koskensalo S, Mecklin JP, Rajamäki K, Palin K, Aaltonen LA. Lynch syndrome-associated and sporadic microsatellite unstable colorectal cancers: different patterns of clonal evolution yield highly similar tumours. Hum Mol Genet 2024; 33:1858-1872. [PMID: 39180486 PMCID: PMC11540923 DOI: 10.1093/hmg/ddae124] [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: 04/08/2024] [Revised: 07/22/2024] [Accepted: 08/13/2024] [Indexed: 08/26/2024] Open
Abstract
Microsatellite unstable colorectal cancer (MSI-CRC) can arise through germline mutations in mismatch repair (MMR) genes in individuals with Lynch syndrome (LS), or sporadically through promoter methylation of the MMR gene MLH1. Despite the different origins of hereditary and sporadic MSI tumours, their genomic features have not been extensively compared. A prominent feature of MMR-deficient genomes is the occurrence of many indels in short repeat sequences, an understudied mutation type due to the technical challenges of variant calling in these regions. In this study, we performed whole genome sequencing and RNA-sequencing on 29 sporadic and 14 hereditary MSI-CRCs. We compared the tumour groups by analysing genome-wide mutation densities, microsatellite repeat indels, recurrent protein-coding variants, signatures of single base, doublet base, and indel mutations, and changes in gene expression. We show that the mutational landscapes of hereditary and sporadic MSI-CRCs, including mutational signatures and mutation densities genome-wide and in microsatellites, are highly similar. Only a low number of differentially expressed genes were found, enriched to interferon-γ regulated immune response pathways. Analysis of the variance in allelic fractions of somatic variants in each tumour group revealed higher clonal heterogeneity in sporadic MSI-CRCs. Our results suggest that the differing molecular origins of MMR deficiency in hereditary and sporadic MSI-CRCs do not result in substantial differences in the mutational landscapes of these tumours. The divergent patterns of clonal evolution between the tumour groups may have clinical implications, as high clonal heterogeneity has been associated with decreased tumour immunosurveillance and reduced responsiveness to immunotherapy.
Collapse
Affiliation(s)
- Samantha Martin
- Medicum/Department of Medical and Clinical Genetics, University of Helsinki, Haartmaninkatu 8, 00014 Helsinki, Finland
- Applied Tumor Genomics Research Program, Research Programs Unit, University of Helsinki, Haartmaninkatu 8, 00014 Helsinki, Finland
| | - Riku Katainen
- Medicum/Department of Medical and Clinical Genetics, University of Helsinki, Haartmaninkatu 8, 00014 Helsinki, Finland
- Applied Tumor Genomics Research Program, Research Programs Unit, University of Helsinki, Haartmaninkatu 8, 00014 Helsinki, Finland
| | - Aurora Taira
- Medicum/Department of Medical and Clinical Genetics, University of Helsinki, Haartmaninkatu 8, 00014 Helsinki, Finland
- Applied Tumor Genomics Research Program, Research Programs Unit, University of Helsinki, Haartmaninkatu 8, 00014 Helsinki, Finland
| | - Niko Välimäki
- Medicum/Department of Medical and Clinical Genetics, University of Helsinki, Haartmaninkatu 8, 00014 Helsinki, Finland
- Applied Tumor Genomics Research Program, Research Programs Unit, University of Helsinki, Haartmaninkatu 8, 00014 Helsinki, Finland
| | - Ari Ristimäki
- Applied Tumor Genomics Research Program, Research Programs Unit, University of Helsinki, Haartmaninkatu 8, 00014 Helsinki, Finland
- Department of Pathology, HUSLAB, HUS Diagnostic Center, University of Helsinki and Helsinki University Hospital, Haartmaninkatu 3, 00290 Helsinki, Finland
| | - Toni Seppälä
- Applied Tumor Genomics Research Program, Research Programs Unit, University of Helsinki, Haartmaninkatu 8, 00014 Helsinki, Finland
- Department of Surgery, Helsinki University Central Hospital, Hospital District of Helsinki and Uusimaa, Haartmaninkatu 4, 00290 Helsinki, Finland
- Department of Gastroenterology and Alimentary Tract Surgery, Tampere University Hospital and TAYS Cancer Centre, Kuntokatu 2, 33520 Tampere, Finland
- Faculty of Medicine and Health Technology, Tampere University, Kalevantie 4, 33100 Tampere, Finland
- iCAN Digital Precision Cancer Medicine Flagship, University of Helsinki, Haartmaninkatu 8, 00014 Helsinki, Finland
| | - Laura Renkonen-Sinisalo
- Applied Tumor Genomics Research Program, Research Programs Unit, University of Helsinki, Haartmaninkatu 8, 00014 Helsinki, Finland
- Department of Surgery, Helsinki University Central Hospital, Hospital District of Helsinki and Uusimaa, Haartmaninkatu 4, 00290 Helsinki, Finland
| | - Anna Lepistö
- Applied Tumor Genomics Research Program, Research Programs Unit, University of Helsinki, Haartmaninkatu 8, 00014 Helsinki, Finland
- Department of Surgery, Helsinki University Central Hospital, Hospital District of Helsinki and Uusimaa, Haartmaninkatu 4, 00290 Helsinki, Finland
| | - Kyösti Tahkola
- Faculty of Medicine and Health Technology, Tampere University, Kalevantie 4, 33100 Tampere, Finland
- Department of Surgery, Central Finland Health Care District, Keskussairaalantie 19, 40620 Jyväskylä, Finland
| | - Anne Mattila
- Department of Surgery, Central Finland Health Care District, Keskussairaalantie 19, 40620 Jyväskylä, Finland
| | - Selja Koskensalo
- The HUCH Gastrointestinal Clinic, Helsinki University Central Hospital, Stenbäckinkatu 9A, 00029 Helsinki, Finland
| | - Jukka-Pekka Mecklin
- Department of Education and Research, The Wellbeing Services of Central Finland, Hoitajatie 1, 40620 Jyväskylä, Finland
- Department of Sport and Health Sciences, University of Jyväskylä, Seminaarinkatu 15, 40014 Jyväskylä, Finland
| | - Kristiina Rajamäki
- Medicum/Department of Medical and Clinical Genetics, University of Helsinki, Haartmaninkatu 8, 00014 Helsinki, Finland
- Applied Tumor Genomics Research Program, Research Programs Unit, University of Helsinki, Haartmaninkatu 8, 00014 Helsinki, Finland
| | - Kimmo Palin
- Medicum/Department of Medical and Clinical Genetics, University of Helsinki, Haartmaninkatu 8, 00014 Helsinki, Finland
- Applied Tumor Genomics Research Program, Research Programs Unit, University of Helsinki, Haartmaninkatu 8, 00014 Helsinki, Finland
- iCAN Digital Precision Cancer Medicine Flagship, University of Helsinki, Haartmaninkatu 8, 00014 Helsinki, Finland
| | - Lauri A Aaltonen
- Medicum/Department of Medical and Clinical Genetics, University of Helsinki, Haartmaninkatu 8, 00014 Helsinki, Finland
- Applied Tumor Genomics Research Program, Research Programs Unit, University of Helsinki, Haartmaninkatu 8, 00014 Helsinki, Finland
- iCAN Digital Precision Cancer Medicine Flagship, University of Helsinki, Haartmaninkatu 8, 00014 Helsinki, Finland
| |
Collapse
|
|
5
|
Hossain SM, Carpenter C, Eccles MR. Genomic and Epigenomic Biomarkers of Immune Checkpoint Immunotherapy Response in Melanoma: Current and Future Perspectives. Int J Mol Sci 2024; 25:7252. [PMID: 39000359 PMCID: PMC11241335 DOI: 10.3390/ijms25137252] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2024] [Revised: 06/25/2024] [Accepted: 06/26/2024] [Indexed: 07/16/2024] Open
Abstract
Immune checkpoint inhibitors (ICIs) demonstrate durable responses, long-term survival benefits, and improved outcomes in cancer patients compared to chemotherapy. However, the majority of cancer patients do not respond to ICIs, and a high proportion of those patients who do respond to ICI therapy develop innate or acquired resistance to ICIs, limiting their clinical utility. The most studied predictive tissue biomarkers for ICI response are PD-L1 immunohistochemical expression, DNA mismatch repair deficiency, and tumour mutation burden, although these are weak predictors of ICI response. The identification of better predictive biomarkers remains an important goal to improve the identification of patients who would benefit from ICIs. Here, we review established and emerging biomarkers of ICI response, focusing on epigenomic and genomic alterations in cancer patients, which have the potential to help guide single-agent ICI immunotherapy or ICI immunotherapy in combination with other ICI immunotherapies or agents. We briefly review the current status of ICI response biomarkers, including investigational biomarkers, and we present insights into several emerging and promising epigenomic biomarker candidates, including current knowledge gaps in the context of ICI immunotherapy response in melanoma patients.
Collapse
Affiliation(s)
- Sultana Mehbuba Hossain
- Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin 9016, New Zealand; (S.M.H.); (C.C.)
- Maurice Wilkins Centre for Molecular Biodiscovery, Level 2, 3A Symonds Street, Auckland 1010, New Zealand
| | - Carien Carpenter
- Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin 9016, New Zealand; (S.M.H.); (C.C.)
| | - Michael R. Eccles
- Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin 9016, New Zealand; (S.M.H.); (C.C.)
- Maurice Wilkins Centre for Molecular Biodiscovery, Level 2, 3A Symonds Street, Auckland 1010, New Zealand
| |
Collapse
|
|
6
|
Sharma S, Singh N, Turk AA, Wan I, Guttikonda A, Dong JL, Zhang X, Opyrchal M. Molecular insights into clinical trials for immune checkpoint inhibitors in colorectal cancer: Unravelling challenges and future directions. World J Gastroenterol 2024; 30:1815-1835. [PMID: 38659481 PMCID: PMC11036501 DOI: 10.3748/wjg.v30.i13.1815] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2023] [Revised: 02/22/2024] [Accepted: 03/13/2024] [Indexed: 04/03/2024] Open
Abstract
Colorectal cancer (CRC) is a complex disease with diverse etiologies and clinical outcomes. Despite considerable progress in development of CRC therapeutics, challenges remain regarding the diagnosis and management of advanced stage metastatic CRC (mCRC). In particular, the five-year survival rate is very low since mCRC is currently rarely curable. Over the past decade, cancer treatment has significantly improved with the introduction of cancer immunotherapies, specifically immune checkpoint inhibitors. Therapies aimed at blocking immune checkpoints such as PD-1, PD-L1, and CTLA-4 target inhibitory pathways of the immune system, and thereby enhance anti-tumor immunity. These therapies thus have shown promising results in many clinical trials alone or in combination. The efficacy and safety of immunotherapy, either alone or in combination with CRC, have been investigated in several clinical trials. Clinical trials, including KEYNOTE-164 and CheckMate 142, have led to Food and Drug Administration approval of the PD-1 inhibitors pembrolizumab and nivolumab, respectively, for the treatment of patients with unresectable or metastatic microsatellite instability-high or deficient mismatch repair CRC. Unfortunately, these drugs benefit only a small percentage of patients, with the benefits of immunotherapy remaining elusive for the vast majority of CRC patients. To this end, primary and secondary resistance to immunotherapy remains a significant issue, and further research is necessary to optimize the use of immunotherapy in CRC and identify biomarkers to predict the response. This review provides a comprehensive overview of the clinical trials involving immune checkpoint inhibitors in CRC. The underlying rationale, challenges faced, and potential future steps to improve the prognosis and enhance the likelihood of successful trials in this field are discussed.
Collapse
Affiliation(s)
- Samantha Sharma
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, United States
| | - Naresh Singh
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, United States
| | - Anita Ahmed Turk
- Division of Hematology/Oncology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, United States
| | - Isabella Wan
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, United States
| | - Akshay Guttikonda
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, United States
| | - Julia Lily Dong
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, United States
| | - Xinna Zhang
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, United States
- Melvin and Bren Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, IN 46202, United States
| | - Mateusz Opyrchal
- Division of Hematology/Oncology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, United States
- Melvin and Bren Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, IN 46202, United States
| |
Collapse
|
|
7
|
Dubey AK, Kaur I, Madaan R, Raheja S, Bala R, Garg M, Kumar S, Lather V, Mittal V, Pandita D, Gundamaraju R, Singla RK, Sharma R. Unlocking the potential of oncology biomarkers: advancements in clinical theranostics. Drug Metab Pers Ther 2024; 39:5-20. [PMID: 38469723 DOI: 10.1515/dmpt-2023-0056] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Accepted: 01/11/2024] [Indexed: 03/13/2024]
Abstract
INTRODUCTION Cancer biomarkers have revolutionized the field of oncology by providing valuable insights into tumor changes and aiding in screening, diagnosis, prognosis, treatment prediction, and risk assessment. The emergence of "omic" technologies has enabled biomarkers to become reliable and accurate predictors of outcomes during cancer treatment. CONTENT In this review, we highlight the clinical utility of biomarkers in cancer identification and motivate researchers to establish a personalized/precision approach in oncology. By extending a multidisciplinary technology-based approach, biomarkers offer an alternative to traditional techniques, fulfilling the goal of cancer therapeutics to find a needle in a haystack. SUMMARY AND OUTLOOK We target different forms of cancer to establish a dynamic role of biomarkers in understanding the spectrum of malignancies and their biochemical and molecular characterization, emphasizing their prospective contribution to cancer screening. Biomarkers offer a promising avenue for the early detection of human cancers and the exploration of novel technologies to predict disease severity, facilitating maximum survival and minimum mortality rates. This review provides a comprehensive overview of the potential of biomarkers in oncology and highlights their prospects in advancing cancer diagnosis and treatment.
Collapse
Affiliation(s)
- Ankit Kumar Dubey
- Joint Laboratory of Artificial Intelligence for Critical Care Medicine, Department of Critical Care Medicine and Institutes for Systems Genetics, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, 34753 Sichuan University , Chengdu, P.R. China
- iGlobal Research and Publishing Foundation, New Delhi, India
| | - Ishnoor Kaur
- Chitkara College of Pharmacy, 154025 Chitkara University Punjab , Rajpura, India
| | - Reecha Madaan
- Chitkara College of Pharmacy, 154025 Chitkara University Punjab , Rajpura, India
| | - Shikha Raheja
- Jan Nayak Ch. Devi Lal Memorial College of Pharmacy, Sirsa, Haryana, India
| | - Rajni Bala
- Chitkara College of Pharmacy, 154025 Chitkara University Punjab , Rajpura, India
| | - Manoj Garg
- Amity Institute of Molecular Medicine & Stem Cell Research, 77282 Amity University, Sector-125 , Noida, India
| | - Suresh Kumar
- Department of Pharmaceutical Sciences and Drug Research, 429174 Punjabi University Patiala , Patiala, India
| | - Viney Lather
- Amity Institute of Pharmacy, 77282 Amity University , Noida, India
| | - Vineet Mittal
- Department of Pharmaceutical Sciences, 29062 Maharshi Dayanand University , Rohtak, Haryana, India
| | - Deepti Pandita
- Department of Pharmaceutics, Delhi Pharmaceutical Sciences and Research University, PushpVihar, 633274 Govt. of NCT of Delhi , New Delhi, India
- Centre for Advanced Formulation and Technology (CAFT), Delhi Pharmaceutical Sciences and Research University, PushpVihar, Govt. of NCT of Delhi, New Delhi, India
| | - Rohit Gundamaraju
- ER Stress and Mucosal Immunology Lab, School of Health Sciences, 8785 University of Tasmania , Launceston, Tasmania, Australia
- School of Medicine, University of California San Francisco, San Francisco, CA, USA
| | - Rajeev K Singla
- Joint Laboratory of Artificial Intelligence for Critical Care Medicine, Department of Critical Care Medicine and Institutes for Systems Genetics, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, 34753 Sichuan University , Chengdu, P.R. China
- School of Pharmaceutical Sciences, 34753 Lovely Professional University , Phagwara, Punjab, India
| | - Rohit Sharma
- Department of Rasa Shastra and Bhaishajya Kalpana, Faculty of Ayurveda, Institute of Medical Sciences, 80095 Banaras Hindu University , Varanasi, Uttar Pradesh, India
| |
Collapse
|
|
8
|
Dal Buono A, Puccini A, Franchellucci G, Airoldi M, Bartolini M, Bianchi P, Santoro A, Repici A, Hassan C. Lynch Syndrome: From Multidisciplinary Management to Precision Prevention. Cancers (Basel) 2024; 16:849. [PMID: 38473212 DOI: 10.3390/cancers16050849] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2024] [Revised: 02/10/2024] [Accepted: 02/19/2024] [Indexed: 03/14/2024] Open
Abstract
BACKGROUND AND AIMS Lynch syndrome (LS) is currently one of the most prevalent hereditary cancer conditions, accounting for 3% of all colorectal cancers and for up to 15% of those with DNA mismatch repair (MMR) deficiency, and it was one of the first historically identified. The understanding of the molecular carcinogenesis of LS tumors has progressed significantly in recent years. We aim to review the most recent advances in LS research and explore genotype-based approaches in surveillance, personalized cancer prevention, and treatment strategies. METHODS PubMed was searched to identify relevant studies, conducted up to December 2023, investigating molecular carcinogenesis in LS, surveillance strategies, cancer prevention, and treatment in LS tumors. RESULTS Multigene panel sequencing is becoming the benchmark in the diagnosis of LS, allowing for the detection of a pathogenic constitutional variant in one of the MMR genes. Emerging data from randomized controlled trials suggest possible preventive roles of resistant starch and/or aspirin in LS. Vaccination with immunogenic frameshift peptides appears to be a promising approach for both the treatment and prevention of LS-associated cancers, as evidenced by pre-clinical and preliminary phase 1/2a studies. CONCLUSIONS Although robust diagnostic algorithms, including prompt testing of tumor tissue for MMR defects and referral for genetic counselling, currently exist for suspected LS in CRC patients, the indications for LS screening in cancer-free individuals still need to be refined and standardized. Investigation into additional genetic and non-genetic factors that may explain residual rates of interval cancers, even in properly screened populations, would allow for more tailored preventive strategies.
Collapse
Affiliation(s)
- Arianna Dal Buono
- Department of Gastroenterology, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Milan, Italy
| | - Alberto Puccini
- Medical Oncology and Haematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Milan, Italy
| | - Gianluca Franchellucci
- Department of Gastroenterology, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Milan, Italy
- Department of Biomedical Sciences, Humanitas University, 20072 Pieve Emanuele, Milan, Italy
| | - Marco Airoldi
- Department of Gastroenterology, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Milan, Italy
- Department of Biomedical Sciences, Humanitas University, 20072 Pieve Emanuele, Milan, Italy
| | - Michela Bartolini
- Department of Gastroenterology, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Milan, Italy
- Department of Biomedical Sciences, Humanitas University, 20072 Pieve Emanuele, Milan, Italy
| | - Paolo Bianchi
- Clinical Analysis Laboratory, Oncological Molecular Genetics Section, IRCCS Humanitas Research Hospital, 20089 Rozzano, Milan, Italy
| | - Armando Santoro
- Medical Oncology and Haematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Milan, Italy
- Department of Biomedical Sciences, Humanitas University, 20072 Pieve Emanuele, Milan, Italy
| | - Alessandro Repici
- Department of Gastroenterology, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Milan, Italy
- Department of Biomedical Sciences, Humanitas University, 20072 Pieve Emanuele, Milan, Italy
| | - Cesare Hassan
- Department of Gastroenterology, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Milan, Italy
- Department of Biomedical Sciences, Humanitas University, 20072 Pieve Emanuele, Milan, Italy
| |
Collapse
|
|
9
|
Pu T, Peddle A, Zhu J, Tejpar S, Verbandt S. Neoantigen identification: Technological advances and challenges. Methods Cell Biol 2023; 183:265-302. [PMID: 38548414 DOI: 10.1016/bs.mcb.2023.06.005] [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: 04/02/2024]
Abstract
Neoantigens have emerged as promising targets for cutting-edge immunotherapies, such as cancer vaccines and adoptive cell therapy. These neoantigens are unique to tumors and arise exclusively from somatic mutations or non-genomic aberrations in tumor proteins. They encompass a wide range of alterations, including genomic mutations, post-transcriptomic variants, and viral oncoproteins. With the advancements in technology, the identification of immunogenic neoantigens has seen rapid progress, raising new opportunities for enhancing their clinical significance. Prediction of neoantigens necessitates the acquisition of high-quality samples and sequencing data, followed by mutation calling. Subsequently, the pipeline involves integrating various tools that can predict the expression, processing, binding, and recognition potential of neoantigens. However, the continuous improvement of computational tools is constrained by the availability of datasets which contain validated immunogenic neoantigens. This review article aims to provide a comprehensive summary of the current knowledge as well as limitations in neoantigen prediction and validation. Additionally, it delves into the origin and biological role of neoantigens, offering a deeper understanding of their significance in the field of cancer immunotherapy. This article thus seeks to contribute to the ongoing efforts to harness neoantigens as powerful weapons in the fight against cancer.
Collapse
Affiliation(s)
- Ting Pu
- Digestive Oncology Unit, KULeuven, Leuven, Belgium
| | | | - Jingjing Zhu
- de Duve Institute, Université catholique de Louvain, Brussels, Belgium
| | | | | |
Collapse
|
|
10
|
Shimozaki K, Nakayama I, Hirota T, Yamaguchi K. Current Strategy to Treat Immunogenic Gastrointestinal Cancers: Perspectives for a New Era. Cells 2023; 12:1049. [PMID: 37048122 PMCID: PMC10093684 DOI: 10.3390/cells12071049] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Revised: 03/15/2023] [Accepted: 03/29/2023] [Indexed: 04/14/2023] Open
Abstract
Since pembrolizumab, an anti-programmed death-1 (PD-1) antibody, showed a dramatic response to immunogenic cancers with microsatellite instability-high (MSI-H) and/or deficient mismatch repair (dMMR) in the pilot clinical trial KEYNOTE-016, subsequent studies have confirmed durable responses of anti-PD-1 inhibitors for MSI-H/dMMR solid tumors. As immunotherapy is described as a "game changer," the therapeutic landscape for MSI-H/dMMR solid tumors including gastrointestinal cancers has changed considerably in the last decade. An MSI/MMR status has been established as the predictive biomarker for immune checkpoint blockades, playing an indispensable role in the clinical practice of patients with MSI-H/dMMR tumors. Immunotherapy is also now investigated for locally advanced MSI-H/dMMR gastrointestinal cancers. Despite this great success, a few populations with MSI-H/dMMR gastrointestinal cancers do not respond to immunotherapy, possibly due to the existence of intrinsic or acquired resistance mechanisms. Clarifying the underlying mechanisms of resistance remains a future task, whereas attempts to overcome resistance and improve the efficacy of immunotherapy are currently ongoing. Herein, we review recent clinical trials with special attention to MSI-H/dMMR gastrointestinal cancers together with basic/translational findings, which provide their rationale, and discuss perspectives for the further therapeutic development of treatment in this field.
Collapse
Affiliation(s)
- Keitaro Shimozaki
- Department of Gastrointestinal Oncology, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo 135-0063, Japan
- Department of Gastroenterology and Hepatology, Division of Internal Medicine, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Izuma Nakayama
- Department of Gastrointestinal Oncology, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo 135-0063, Japan
| | - Toru Hirota
- Department of Experimental Pathology, Cancer Institute of the Japanese Foundation for Cancer Research, Tokyo 135-8550, Japan
| | - Kensei Yamaguchi
- Department of Gastrointestinal Oncology, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo 135-0063, Japan
| |
Collapse
|
|
11
|
Saito Y, Fujiwara Y, Miyamoto Y, Ohnishi K, Nakashima Y, Tabata Y, Baba H, Komohara Y. CD169 + sinus macrophages in regional lymph nodes do not predict mismatch-repair status of patients with colorectal cancer. Cancer Med 2023; 12:10199-10211. [PMID: 36846928 DOI: 10.1002/cam4.5747] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Revised: 02/01/2023] [Accepted: 02/03/2023] [Indexed: 03/01/2023] Open
Abstract
AIMS Mismatch-repair deficiency and microsatellite instability-high (dMMR/MSI-H) colorectal cancer (CRC) is treated with programmed death (PD)-1 antibody regardless of PD-ligand (L)1 expression in tumor cells. We previously found that abundant CD169+ macrophages in regional lymph node (RLN) sinuses and CD8+ tumor-infiltrating lymphocytes (TILs) positively correlated in CRC and were associated with a favorable prognosis. However, associations between dMMR/MSI-H CRC and CD8+ TILs or prognoses vary among studies. In this study, we attempted to compare the association between MMR status, CD169+ macrophages in RLNs, CD8+ TILs, PD-L1 scores, and prognoses in CRC. METHODS AND RESULTS We immunostained 83 surgically resected CRC tumors that we previously analyzed for MMR proteins, and identified 9 that were dMMR. The number of CD169+ macrophages in RLNs and CD8+ TILs significantly correlated with overall survival, whereas MMR status did not. The number of cells positive for the TIL markers CD3, CD4, CD8, and TIA-1, and macrophage markers CD68 and CD169 in RLNs did not significantly differ between groups according to MMR status. Furthermore, combined positive scores (CPS) for PD-L1 expression in five of nine dMMR CRCs were all <1. We found that dMMR in CRC did not correlate with numbers of CD169+ macrophages in RLNs or CD8+ TILs. CONCLUSIONS CRC with CD169+ macrophages in RLNs and abundant CD8+ TILs indicates a better prognosis and it should be immunologically classified as a different antitumor group from dMMR CRC.
Collapse
Affiliation(s)
- Yoichi Saito
- Department of Cell Pathology, Graduate School of Medical Sciences, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.,Laboratory of Biomaterials, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, Japan.,Laboratory of Bioengineering, Faculty of Advanced Science and Technology, Kumamoto University, Kumamoto, Japan.,Japan Society for the Promotion of Science, Tokyo, Japan
| | - Yukio Fujiwara
- Department of Cell Pathology, Graduate School of Medical Sciences, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Yuji Miyamoto
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Koji Ohnishi
- Department of Cell Pathology, Graduate School of Medical Sciences, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Yuta Nakashima
- Laboratory of Bioengineering, Faculty of Advanced Science and Technology, Kumamoto University, Kumamoto, Japan.,Institute of Industrial Nanomaterials, Kumamoto University, Kumamoto, Japan.,International Research Organization for Advanced Science and Technology, Kumamoto University, Kumamoto, Japan.,Fusion Oriented Research for Disruptive Science and Technology, Japan Science and Technology Agency, Saitama, Japan
| | - Yasuhiko Tabata
- Laboratory of Biomaterials, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, Japan
| | - Hideo Baba
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Yoshihiro Komohara
- Department of Cell Pathology, Graduate School of Medical Sciences, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
| |
Collapse
|
|
12
|
Plewa N, Poncette L, Blankenstein T. Generation of TGFβR2(-1) neoantigen-specific HLA-DR4-restricted T cell receptors for cancer therapy. J Immunother Cancer 2023; 11:jitc-2022-006001. [PMID: 36822673 PMCID: PMC9950979 DOI: 10.1136/jitc-2022-006001] [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] [Accepted: 02/06/2023] [Indexed: 02/25/2023] Open
Abstract
BACKGROUND Adoptive transfer of patient's T cells, engineered to express a T cell receptor (TCR) with defined novel antigen specificity, is a convenient form of cancer therapy. In most cases, major histocompatibility complex (MHC) I-restricted TCRs are expressed in CD8+ T cells and the development of CD4+ T cells engineered to express an MHC II-restricted TCR lacks behind. Critical is the choice of the target antigen, whether the epitope is efficiently processed and binds with high affinity to MHC molecules. A mutation in the transforming growth factor β receptor 2 (TGFβR2(-1)) gene creates a frameshift peptide caused by the deletion of one adenine (-1) within a microsatellite sequence. This somatic mutation is recurrent in microsatellite instable colorectal and gastric cancers and, therefore, is a truly tumor-specific antigen detected in many patients. METHODS ABabDR4 mice, which express a diverse human TCR repertoire restricted to human MHC II molecule HLA-DRA/DRB1*0401 (HLA-DR4), were immunized with the TGFβR2(-1) peptide and TGFβR2(-1)-specific TCRs were isolated from responding CD4+ T cells. The TGFβR2(-1)-specific TCRs were expressed in human CD4+ T cells and their potency and safety profile were assessed by co-cultures and other functional assays. RESULTS We demonstrated that TGFβR2(-1) neoantigen is immunogenic and elicited CD4+ T cell responses in ABabDR4 mice. When expressed in human CD4+ T cells, the HLA-DR4 restricted TGFβR2(-1)-specific TCRs induced IFNy expression at low TGFβR2(-1) peptide amounts. The TGFβR2(-1)-specific TCRs recognized HLA-DR4+ lymphoblastoid cells, which endogenously processed and presented the neoantigen, and colorectal cancer cell lines SW48 and HCT116 naturally expressing the TGFβR2(-1) mutation. No MHC II alloreactivity or cross-reactivity to peptides with a similar TCR-recognition motif were observed, indicating the safety of the TCRs. CONCLUSIONS The data suggest that HLA-DR4-restricted TCRs specific for the TGFβR2(-1) recurrent neoantigen can be valuable candidates for adoptive T cell therapy of a sizeable number of patients with cancer.
Collapse
Affiliation(s)
- Natalia Plewa
- Max Delbruck Centre for Molecular Medicine, Berlin, Germany
| | - Lucia Poncette
- Max Delbruck Centre for Molecular Medicine, Berlin, Germany
| | | |
Collapse
|
|
13
|
Wang Q, Shen X, Chen G, Du J. How to overcome resistance to immune checkpoint inhibitors in colorectal cancer: From mechanisms to translation. Int J Cancer 2023. [PMID: 36752642 DOI: 10.1002/ijc.34464] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2022] [Revised: 01/14/2023] [Accepted: 02/01/2023] [Indexed: 02/09/2023]
Abstract
Immunotherapy, especially with immune checkpoint inhibitors (ICIs), has shown advantages in cancer treatment and is a new hope for patients who have failed multiline therapy. However, in colorectal cancer (CRC), the benefit is limited to a small subset of patients with microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR) metastatic CRC (mCRC). In addition, 45% to 60% of dMMR/MSI-H mCRC patients showed primary or acquired resistance to ICIs. This means that these patients may have potential unknown pathways mediating immune escape. Almost all mismatch repair-proficient (pMMR) or microsatellite-stable (MSS) mCRC patients do not benefit from ICIs. In this review, we discuss the mechanisms of action of ICIs and their current status in CRC. We then discuss the mechanisms of primary and acquired resistance to ICIs in CRC. Finally, we discuss promising therapeutic strategies to overcome resistance to ICIs in the clinic.
Collapse
Affiliation(s)
- Qianyu Wang
- Medical Department of General Surgery, The 1st Medical Center, Chinese PLA General Hospital, Beijing, China.,The Second School of Clinical Medicine, Shanxi Medical University, Taiyuan, China
| | - Xiaofei Shen
- Department of General Surgery, Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China
| | - Gang Chen
- Medical Department of General Surgery, The 1st Medical Center, Chinese PLA General Hospital, Beijing, China.,Department of General Surgery, The 7th Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Junfeng Du
- Medical Department of General Surgery, The 1st Medical Center, Chinese PLA General Hospital, Beijing, China.,Department of General Surgery, The 7th Medical Center, Chinese PLA General Hospital, Beijing, China.,The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China
| |
Collapse
|
|
14
|
Biswas K, Mohammed A, Sharan SK, Shoemaker RH. Genetically engineered mouse models for hereditary cancer syndromes. Cancer Sci 2023; 114:1800-1815. [PMID: 36715493 PMCID: PMC10154891 DOI: 10.1111/cas.15737] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Revised: 01/21/2023] [Accepted: 01/25/2023] [Indexed: 01/31/2023] Open
Abstract
Advances in molecular diagnostics have led to improved diagnosis and molecular understanding of hereditary cancers in the clinic. Improving the management, treatment, and potential prevention of cancers in carriers of predisposing mutations requires preclinical experimental models that reflect the key pathogenic features of the specific syndrome associated with the mutations. Numerous genetically engineered mouse (GEM) models of hereditary cancer have been developed. In this review, we describe the models of Lynch syndrome and hereditary breast and ovarian cancer syndrome, the two most common hereditary cancer predisposition syndromes. We focus on Lynch syndrome models as illustrative of the potential for using mouse models to devise improved approaches to prevention of cancer in a high-risk population. GEM models are an invaluable tool for hereditary cancer models. Here, we review GEM models for some hereditary cancers and their potential use in cancer prevention studies.
Collapse
Affiliation(s)
- Kajal Biswas
- Chemopreventive Agent Development Research Group, Division of Cancer Prevention, National Cancer Institute, Rockville, Maryland, USA
| | - Altaf Mohammed
- Chemopreventive Agent Development Research Group, Division of Cancer Prevention, National Cancer Institute, Rockville, Maryland, USA
| | - Shyam K Sharan
- Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, Maryland, USA
| | - Robert H Shoemaker
- Chemopreventive Agent Development Research Group, Division of Cancer Prevention, National Cancer Institute, Rockville, Maryland, USA
| |
Collapse
|
|
15
|
Chan EM, Foster KJ, Bass AJ. WRN Is a Promising Synthetic Lethal Target for Cancers with Microsatellite Instability (MSI). Cancer Treat Res 2023; 186:313-328. [PMID: 37978143 DOI: 10.1007/978-3-031-30065-3_17] [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: 11/19/2023]
Abstract
Microsatellite instability (MSI), a type of genetic hypermutability arising from impaired DNA mismatch repair (MMR), is observed in approximately 3% of all cancers. Preclinical work has identified the RecQ helicase WRN as a promising synthetic lethal target for patients with MSI cancers. WRN depletion substantially impairs the viability of MSI, but not microsatellite stable (MSS), cells. Experimental evidence suggests that this synthetic lethal phenotype is driven by numerous TA dinucleotide repeats that undergo expansion mutations in the setting of long-standing MMR deficiency. The lengthening of TA repeats increases their propensity to form secondary DNA structures that require WRN to resolve. In the absence of WRN helicase activity, these unresolved DNA secondary structures stall DNA replication forks and induce catastrophic DNA damage.
Collapse
Affiliation(s)
- Edmond M Chan
- Department of Medicine, Division of Hematology and Oncology, Columbia University, New York, USA.
- Herbert Irving Comprehensive Cancer Center, Columbia University, New York, USA.
- Broad Institute of MIT and Harvard, Cambridge, USA.
- New York Genome Center, New York, USA.
| | | | - Adam J Bass
- Novartis Institutes for BioMedical Research, Cambridge, USA
| |
Collapse
|
|
16
|
Song JH, Lee Y, Heo J, Son SY, Hur H, Han SU. Secondary Primary Cancer after Primary Gastric Cancer: Literature Review and Big Data Analysis Using the Health Insurance Review and Assessment Service (HIRA) Database of Republic of Korea. Cancers (Basel) 2022; 14:6165. [PMID: 36551649 PMCID: PMC9776911 DOI: 10.3390/cancers14246165] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Revised: 12/13/2022] [Accepted: 12/13/2022] [Indexed: 12/15/2022] Open
Abstract
Advances in cancer screening and early detection, as well as improvements in surgical techniques and therapeutics, have contributed to decreasing gastric cancer mortality. The number of gastric cancer survivors continues to rise; however, long-term follow-up has revealed an increase in the risk of post-gastrectomy symptoms or other health problems, such as extra-gastric secondary primary cancer (SPC), in these survivors. Therefore, evidence-based screening for new primary cancer is needed in these populations; however, the incidence of SPC varies by country or continent and its characteristics have not been clearly reported. The characteristics of SPC are of increasing interest to both treatment providers and gastric cancer survivors; thus, this literature review explores not only the epidemiology and biology of SPC but also clinical and biological factors that influence its prognosis.
Collapse
Affiliation(s)
- Jeong Ho Song
- Department of Surgery, Ajou University School of Medicine, Suwon 16499, Republic of Korea
| | - Yeonkyoung Lee
- Department of Surgery, Ajou University School of Medicine, Suwon 16499, Republic of Korea
| | - Jaesung Heo
- Department of Radiation Oncology, Ajou University School of Medicine, Suwon 16499, Republic of Korea
| | - Sang-Yong Son
- Department of Surgery, Ajou University School of Medicine, Suwon 16499, Republic of Korea
| | - Hoon Hur
- Department of Surgery, Ajou University School of Medicine, Suwon 16499, Republic of Korea
| | - Sang-Uk Han
- Department of Surgery, Ajou University School of Medicine, Suwon 16499, Republic of Korea
| |
Collapse
|
|
17
|
Tumor antigens and vaccines in colorectal cancer. MEDICINE IN DRUG DISCOVERY 2022. [DOI: 10.1016/j.medidd.2022.100144] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
|
|
18
|
Ghazi B, El Ghanmi A, Kandoussi S, Ghouzlani A, Badou A. CAR T-cells for colorectal cancer immunotherapy: Ready to go? Front Immunol 2022; 13:978195. [PMID: 36458008 PMCID: PMC9705989 DOI: 10.3389/fimmu.2022.978195] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2022] [Accepted: 10/14/2022] [Indexed: 08/12/2023] Open
Abstract
Chimeric antigen receptor (CAR) T-cells represent a new genetically engineered cell-based immunotherapy tool against cancer. The use of CAR T-cells has revolutionized the therapeutic approach for hematological malignancies. Unfortunately, there is a long way to go before this treatment can be developed for solid tumors, including colorectal cancer. CAR T-cell therapy for colorectal cancer is still in its early stages, and clinical data are scarce. Major limitations of this therapy include high toxicity, relapses, and an impermeable tumor microenvironment for CAR T-cell therapy in colorectal cancer. In this review, we summarize current knowledge, highlight challenges, and discuss perspectives regarding CAR T-cell therapy in colorectal cancer.
Collapse
Affiliation(s)
- Bouchra Ghazi
- Faculty of Medicine, Mohammed VI University of Health Sciences (UM6SS), Casablanca, Morocco
| | - Adil El Ghanmi
- Mohammed VI International University Hospital, Faculty of Medicine, Mohammed VI University of Health Sciences (UM6SS), Casablanca, Morocco
| | - Sarah Kandoussi
- Immuno-Genetics and Human Pathology Laboratory, Faculty of Medicine and Pharmacy, Hassan II University, Casablanca, Morocco
| | - Amina Ghouzlani
- Immuno-Genetics and Human Pathology Laboratory, Faculty of Medicine and Pharmacy, Hassan II University, Casablanca, Morocco
| | - Abdallah Badou
- Immuno-Genetics and Human Pathology Laboratory, Faculty of Medicine and Pharmacy, Hassan II University, Casablanca, Morocco
| |
Collapse
|
|
19
|
Lynch Syndrome: From Carcinogenesis to Prevention Interventions. Cancers (Basel) 2022; 14:cancers14174102. [PMID: 36077639 PMCID: PMC9454739 DOI: 10.3390/cancers14174102] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2022] [Revised: 08/23/2022] [Accepted: 08/23/2022] [Indexed: 11/25/2022] Open
Abstract
Simple Summary Promoting proper preventive interventions to reduce morbidity and mortality is one of the most important challenges pertaining to inherited conditions. Lynch syndrome (LS) is an inherited disorder that predisposes to several kinds of tumor and is responsible for a relevant proportion of human colorectal and endometrial cancers. Recent knowledge has allowed for a better understanding of the genetic cause, pathogenesis, underlying immunological mechanisms, epidemiological distribution, and prevalence of this disease. This opens up unpredictable perspectives of translating such knowledge into validated programs for prevention and surveillance, in order to reduce the health impact of this disease through medical interventions before cancer development. In our review, we summarize the updated guidelines of the screening, surveillance, and risk-reducing strategies for LS patients. Moreover, we present novel opportunities in the treatment and prevention of LS patients through harnessing the immune system using immunocheckpoint inhibitors and vaccines. Abstract Lynch syndrome (LS) is the most common inherited disorder responsible for an increased risk of developing cancers at different sites, most frequently in the gastrointestinal and genitourinary tracts, caused by a germline pathogenic variant affecting the DNA mismatch repair system. Surveillance and risk-reducing procedures are currently available and warranted for LS patients, depending on underlying germline mutation, and are focused on relevant targets for early cancer diagnosis or primary prevention. Although pharmacological approaches for preventing LS-associated cancer development were started many years ago, to date, aspirin remains the most studied drug intervention and the only one suggested by the main surveillance guidelines, despite the conflicting findings. Furthermore, we also note that remarkable advances in anticancer drug discovery have given a significant boost to the application of novel immunological strategies such as immunocheckpoint inhibitors and vaccines, not only for cancer treatment, but also in a preventive setting. In this review, we outline the clinical, biologic, genetic, and morphological features of LS as well as the recent three-pathways carcinogenesis model. Furthermore, we provide an update on the dedicated screening, surveillance, and risk-reducing strategies for LS patients and describe emerging opportunities of harnessing the immune system.
Collapse
|
|
20
|
Alarcon NO, Jaramillo M, Mansour HM, Sun B. Therapeutic Cancer Vaccines—Antigen Discovery and Adjuvant Delivery Platforms. Pharmaceutics 2022; 14:pharmaceutics14071448. [PMID: 35890342 PMCID: PMC9325128 DOI: 10.3390/pharmaceutics14071448] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2022] [Revised: 06/28/2022] [Accepted: 06/30/2022] [Indexed: 12/15/2022] Open
Abstract
For decades, vaccines have played a significant role in protecting public and personal health against infectious diseases and proved their great potential in battling cancers as well. This review focused on the current progress of therapeutic subunit vaccines for cancer immunotherapy. Antigens and adjuvants are key components of vaccine formulations. We summarized several classes of tumor antigens and bioinformatic approaches of identification of tumor neoantigens. Pattern recognition receptor (PRR)-targeting adjuvants and their targeted delivery platforms have been extensively discussed. In addition, we emphasized the interplay between multiple adjuvants and their combined delivery for cancer immunotherapy.
Collapse
Affiliation(s)
- Neftali Ortega Alarcon
- Skaggs Pharmaceutical Sciences Center, College of Pharmacy, The University of Arizona, Tucson, AZ 85721, USA; (N.O.A.); (M.J.); (H.M.M.)
| | - Maddy Jaramillo
- Skaggs Pharmaceutical Sciences Center, College of Pharmacy, The University of Arizona, Tucson, AZ 85721, USA; (N.O.A.); (M.J.); (H.M.M.)
| | - Heidi M. Mansour
- Skaggs Pharmaceutical Sciences Center, College of Pharmacy, The University of Arizona, Tucson, AZ 85721, USA; (N.O.A.); (M.J.); (H.M.M.)
- The University of Arizona Cancer Center, Tucson, AZ 85721, USA
- Department of Medicine, College of Medicine, The University of Arizona, Tucson, AZ 85724, USA
- BIO5 Institute, The University of Arizona, Tucson, AZ 85721, USA
| | - Bo Sun
- Skaggs Pharmaceutical Sciences Center, College of Pharmacy, The University of Arizona, Tucson, AZ 85721, USA; (N.O.A.); (M.J.); (H.M.M.)
- The University of Arizona Cancer Center, Tucson, AZ 85721, USA
- BIO5 Institute, The University of Arizona, Tucson, AZ 85721, USA
- Correspondence: ; Tel.: +1-520-621-6420
| |
Collapse
|
|
21
|
Lang F, Schrörs B, Löwer M, Türeci Ö, Sahin U. Identification of neoantigens for individualized therapeutic cancer vaccines. Nat Rev Drug Discov 2022; 21:261-282. [PMID: 35105974 PMCID: PMC7612664 DOI: 10.1038/s41573-021-00387-y] [Citation(s) in RCA: 271] [Impact Index Per Article: 90.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/13/2021] [Indexed: 02/07/2023]
Abstract
Somatic mutations in cancer cells can generate tumour-specific neoepitopes, which are recognized by autologous T cells in the host. As neoepitopes are not subject to central immune tolerance and are not expressed in healthy tissues, they are attractive targets for therapeutic cancer vaccines. Because the vast majority of cancer mutations are unique to the individual patient, harnessing the full potential of this rich source of targets requires individualized treatment approaches. Many computational algorithms and machine-learning tools have been developed to identify mutations in sequence data, to prioritize those that are more likely to be recognized by T cells and to design tailored vaccines for every patient. In this Review, we fill the gaps between the understanding of basic mechanisms of T cell recognition of neoantigens and the computational approaches for discovery of somatic mutations and neoantigen prediction for cancer immunotherapy. We present a new classification of neoantigens, distinguishing between guarding, restrained and ignored neoantigens, based on how they confer proficient antitumour immunity in a given clinical context. Such context-based differentiation will contribute to a framework that connects neoantigen biology to the clinical setting and medical peculiarities of cancer, and will enable future neoantigen-based therapies to provide greater clinical benefit.
Collapse
Affiliation(s)
- Franziska Lang
- TRON Translational Oncology, Mainz, Germany
- Faculty of Biology, Johannes Gutenberg University Mainz, Mainz, Germany
| | | | | | | | - Ugur Sahin
- BioNTech, Mainz, Germany.
- University Medical Center, Johannes Gutenberg University, Mainz, Germany.
| |
Collapse
|
|
22
|
Mas-Ponte D, McCullough M, Supek F. Spectrum of DNA mismatch repair failures viewed through the lens of cancer genomics and implications for therapy. Clin Sci (Lond) 2022; 136:383-404. [PMID: 35274136 PMCID: PMC8919091 DOI: 10.1042/cs20210682] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2021] [Revised: 02/02/2022] [Accepted: 02/28/2022] [Indexed: 12/15/2022]
Abstract
Genome sequencing can be used to detect DNA repair failures in tumors and learn about underlying mechanisms. Here, we synthesize findings from genomic studies that examined deficiencies of the DNA mismatch repair (MMR) pathway. The impairment of MMR results in genome-wide hypermutation and in the 'microsatellite instability' (MSI) phenotype-occurrence of indel mutations at short tandem repeat (microsatellite) loci. The MSI status of tumors was traditionally assessed by molecular testing of a selected set of MS loci or by measuring MMR protein expression levels. Today, genomic data can provide a more complete picture of the consequences on genomic instability. Multiple computational studies examined somatic mutation distributions that result from failed DNA repair pathways in tumors. These include analyzing the commonly studied trinucleotide mutational spectra of single-nucleotide variants (SNVs), as well as of other features such as indels, structural variants, mutation clusters and regional mutation rate redistribution. The identified mutation patterns can be used to rigorously measure prevalence of MMR failures across cancer types, and potentially to subcategorize the MMR deficiencies. Diverse data sources, genomic and pre-genomic, from human and from experimental models, suggest there are different ways in which MMR can fail, and/or that the cell-type or genetic background may result in different types of MMR mutational patterns. The spectrum of MMR failures may direct cancer evolution, generating particular sets of driver mutations. Moreover, MMR affects outcomes of therapy by DNA damaging drugs, antimetabolites, nonsense-mediated mRNA decay (NMD) inhibitors, and immunotherapy by promoting either resistance or sensitivity, depending on the type of therapy.
Collapse
Affiliation(s)
- David Mas-Ponte
- Genome Data Science, Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute for Science and Technology, Baldiri Reixac 10, Barcelona 08028, Spain
| | - Marcel McCullough
- Genome Data Science, Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute for Science and Technology, Baldiri Reixac 10, Barcelona 08028, Spain
| | - Fran Supek
- Genome Data Science, Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute for Science and Technology, Baldiri Reixac 10, Barcelona 08028, Spain
- Catalan Institution for Research and Advanced Studies (ICREA), Pg Lluís Companys, 23, Barcelona 08010, Spain
| |
Collapse
|
|
23
|
Neoantigen: A Promising Target for the Immunotherapy of Colorectal Cancer. DISEASE MARKERS 2022; 2022:8270305. [PMID: 35211210 PMCID: PMC8863477 DOI: 10.1155/2022/8270305] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Accepted: 01/28/2022] [Indexed: 02/05/2023]
Abstract
At present, there are various treatment strategies for colorectal cancer, including surgery, chemotherapy, radiotherapy, and targeted therapy. In recent years, with the continuous development of immunotherapy, immune checkpoint inhibitors (ICIs) can significantly improve the treatment of advanced colorectal cancer patients with high levels of microsatellite instability. In addition to ICIs, neoantigens, as a class of tumor-specific antigens (TSA), are regarded as new immunotherapy targets for many cancer species and are being explored for antitumor therapy. Immunotherapy strategies based on neoantigens include tumor vaccines and adoptive cell therapy (ACT). These methods aim to eliminate tumor cells by enhancing the immune response of host T-cells to neoantigens. In addition, for MSS colorectal cancer, such “cold tumors” with low mutation rates and stable microsatellites are not sensitive to ICIs, whereas neoantigens could provide a promising immunotherapeutic avenue. In this review, we summarized the current status of colorectal cancer neoantigen prediction and current clinical trials of neoantigens and discussed the difficulties and limitations of neoantigens-based therapies for the treatment of CRC.
Collapse
|
|
24
|
Hu H, Kang L, Zhang J, Wu Z, Wang H, Huang M, Lan P, Wu X, Wang C, Cao W, Hu J, Huang Y, Huang L, Wang H, Shi L, Cai Y, Shen C, Ling J, Xie X, Cai Y, He X, Dou R, Zhou J, Ma T, Zhang X, Luo S, Deng W, Ling L, Liu H, Deng Y. Neoadjuvant PD-1 blockade with toripalimab, with or without celecoxib, in mismatch repair-deficient or microsatellite instability-high, locally advanced, colorectal cancer (PICC): a single-centre, parallel-group, non-comparative, randomised, phase 2 trial. Lancet Gastroenterol Hepatol 2021; 7:38-48. [PMID: 34688374 DOI: 10.1016/s2468-1253(21)00348-4] [Citation(s) in RCA: 160] [Impact Index Per Article: 40.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2021] [Revised: 09/15/2021] [Accepted: 09/16/2021] [Indexed: 12/22/2022]
Abstract
BACKGROUND PD-1 blockade is highly effective in patients with mismatch repair-deficient or microsatellite instability-high metastatic colorectal cancer. The role of single-agent PD-1 blockade in the neoadjuvant setting for resectable mismatch repair-deficient or microsatellite instability-high colorectal cancer remains unclear. We investigated the efficacy and safety of PD-1 blockade with toripalimab, with or without the COX-2 inhibitor celecoxib, as neoadjuvant treatment for mismatch repair-deficient or microsatellite instability-high, locally advanced, colorectal cancers. METHODS The PD-1 Inhibitor in Microsatellite Instability Colorectal Cancer (PICC) trial was a single-centre, open-label, parallel-group, non-comparative, randomised, phase 2 study undertaken at the Sixth Affiliated Hospital of Sun Yat-sen University (Guangzhou, China). Eligible patients were aged 18-75 years, had histologically confirmed mismatch repair-deficient or microsatellite instability-high colorectal cancer, had clinical stage T3-T4 or any T with lymph node positivity (N+), Eastern Cooperative Oncology Group performance score of 0 or 1, and adequate haematological, hepatic, and renal function. Participants were randomly assigned (1:1), without any stratification or balanced blocking, to receive toripalimab 3 mg/kg intravenously on day 1, with or without celecoxib 200 mg orally twice daily from day 1 to 14 of each 14-day cycle, for six cycles before surgical resection. Adjuvant treatment with toripalimab with or without celecoxib was permitted at the investigators' discretion. The primary endpoint was the proportion of patients with pathological complete response, defined as tumours without any viable tumour cells in the resected primary tumour sample and all sampled regional lymph nodes. All efficacy and safety analyses were assessed in the modified intention-to-treat population, which included all patients who were randomly assigned to treatment and who received at least one dose of toripalimab. This trial is registered with ClinicalTrials.gov, NCT03926338, and is ongoing. FINDINGS Between May 1, 2019, and April 1, 2021, 53 patients were screened, of whom 34 were randomly assigned to either the toripalimab plus celecoxib group (n=17) or the toripalimab monotherapy group (n=17). As of data cutoff (Aug 10, 2021), median follow-up was 14·9 months (IQR 8·8-17·0). All patients received study treatment and underwent surgical resection; there were no treatment-related surgical delays. All 34 patients had an R0 resection (>1 mm resection margin). 15 of 17 patients (88% [95% CI 64-99]) in the toripalimab plus celecoxib group and 11 of 17 patients (65% [38-86]) in the toripalimab monotherapy group had a pathological complete response. All patients continued to receive adjuvant toripalimab with or without celecoxib for a total perioperative duration of 6 months and were alive and free of recurrence at data cutoff. During neoadjuvant treatment, ten (59%) patients in the toripalimab plus celecoxib group and ten (59%) in the toripalimab monotherapy group had grade 1-2 treatment-related adverse events. Only one (3%) of 34 patients, who was in the toripalimab plus celecoxib group, had a grade 3 or higher treatment-related adverse event during the neoadjuvant phase, which was grade 3 increased aspartate aminotransferase levels. In the adjuvant phase, only one (3%) of 34 patients, who was in the toripalimab monotherapy group, had a grade 3 or higher treatment-related adverse events, which was grade 3 increased aspartate aminotransferase and alanine aminotransferase levels. INTERPRETATION Neoadjuvant toripalimab with or without celecoxib could be a potential therapeutic option for patients with mismatch repair deficient or microsatellite instability-high, locally advanced, colorectal cancer. This treatment was associated with a high pathological complete response rate and an acceptable safety profile, which did not compromise surgery. Longer term follow-up is needed to assess effects on survival-related endpoints. FUNDING The National Key R&D Program of China, the National Natural Science Foundation of China, and the Chinese Society of Clinical Oncology-Junshi Biosciences Oncology Immunity Research. TRANSLATION For the Chinese translation of the abstract see Supplementary Materials section.
Collapse
Affiliation(s)
- Huabin Hu
- Department of Medical Oncology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, Guangdong Research Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Liang Kang
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, Guangdong Research Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Department of Colorectal Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Jianwei Zhang
- Department of Medical Oncology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, Guangdong Research Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Zehua Wu
- Department of Medical Oncology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, Guangdong Research Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Hui Wang
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, Guangdong Research Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Department of Colorectal Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Meijin Huang
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, Guangdong Research Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Department of Colorectal Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Ping Lan
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, Guangdong Research Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Department of Colorectal Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Xiaojian Wu
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, Guangdong Research Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Department of Colorectal Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Chao Wang
- Department of Pathology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Wuteng Cao
- Department of Radiology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Jiancong Hu
- Department of Endoscopic Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Yan Huang
- Department of Pathology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Liang Huang
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, Guangdong Research Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Department of Colorectal Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Huaiming Wang
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, Guangdong Research Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Department of Colorectal Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Lishuo Shi
- Clinical Research Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Yue Cai
- Department of Medical Oncology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, Guangdong Research Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Cailu Shen
- Department of Medical Oncology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, Guangdong Research Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Jiayu Ling
- Department of Medical Oncology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, Guangdong Research Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Xiaoyu Xie
- Department of Medical Oncology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, Guangdong Research Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Yonghua Cai
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, Guangdong Research Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Department of Colorectal Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Xiaowen He
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, Guangdong Research Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Department of Colorectal Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Ruoxu Dou
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, Guangdong Research Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Department of Colorectal Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Jiaming Zhou
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, Guangdong Research Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Department of Colorectal Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Tenghui Ma
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, Guangdong Research Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Department of Colorectal Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Xingwei Zhang
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, Guangdong Research Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Department of Colorectal Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Shuangling Luo
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, Guangdong Research Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Department of Colorectal Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Weihao Deng
- Department of Pathology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Li Ling
- Department of Medical Statistics, School of Public Health, Center for Migrant Health Policy, Sun Yat-sen University, Guangzhou, China
| | - Hao Liu
- Biostatistics Shared Resource, Rutgers Cancer Institute of New Jersey, Department of Biostatistics and Epidemiology, Rutgers School of Public Health, Brunswick, NJ, USA
| | - Yanhong Deng
- Department of Medical Oncology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, Guangdong Research Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
| |
Collapse
|
|
25
|
Roudko V, Cimen Bozkus C, Greenbaum B, Lucas A, Samstein R, Bhardwaj N. Lynch Syndrome and MSI-H Cancers: From Mechanisms to "Off-The-Shelf" Cancer Vaccines. Front Immunol 2021; 12:757804. [PMID: 34630437 PMCID: PMC8498209 DOI: 10.3389/fimmu.2021.757804] [Citation(s) in RCA: 51] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Accepted: 09/08/2021] [Indexed: 12/22/2022] Open
Abstract
Defective DNA mismatch repair (dMMR) is associated with many cancer types including colon, gastric, endometrial, ovarian, hepatobiliary tract, urinary tract, brain and skin cancers. Lynch syndrome - a hereditary cause of dMMR - confers increased lifetime risk of malignancy in different organs and tissues. These Lynch syndrome pathogenic alleles are widely present in humans at a 1:320 population frequency of a single allele and associated with an up to 80% risk of developing microsatellite unstable cancer (microsatellite instability - high, or MSI-H). Advanced MSI-H tumors can be effectively treated with checkpoint inhibitors (CPI), however, that has led to response rates of only 30-60% despite their high tumor mutational burden and favorable immune gene signatures in the tumor microenvironment (TME). We and others have characterized a subset of MSI-H associated highly recurrent frameshift mutations that yield shared immunogenic neoantigens. These frameshifts might serve as targets for off-the-shelf cancer vaccine designs. In this review we discuss the current state of research around MSI-H cancer vaccine development, its application to MSI-H and Lynch syndrome cancer patients and the utility of MSI-H as a biomarker for CPI therapy. We also summarize the tumor intrinsic mechanisms underlying the high occurrence rates of certain frameshifts in MSI-H. Finally, we provide an overview of pivotal clinical trials investigating MSI-H as a biomarker for CPI therapy and MSI-H vaccines. Overall, this review aims to inform the development of novel research paradigms and therapeutics.
Collapse
Affiliation(s)
- Vladimir Roudko
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States.,Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States.,Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Cansu Cimen Bozkus
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States.,Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Benjamin Greenbaum
- Epidemiology and Biostatistics, Computational Oncology program, Memorial Sloan Kettering Cancer Center, New York, NY, United States.,Physiology, Biophysics & Systems Biology, Weill Cornell Medical College, New York, NY, United States
| | - Aimee Lucas
- Henry D. Janowitz Division of Gastroenterology, Samuel D. Bronfman Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Robert Samstein
- Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States.,Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States.,Department of Radiation Oncology, Mount Sinai Hospital, New York, NY, United States
| | - Nina Bhardwaj
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States.,Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| |
Collapse
|
|
26
|
Hwang HS, Kim D, Choi J. Distinct mutational profile and immune microenvironment in microsatellite-unstable and POLE-mutated tumors. J Immunother Cancer 2021; 9:e002797. [PMID: 34607897 PMCID: PMC8491424 DOI: 10.1136/jitc-2021-002797] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/20/2021] [Indexed: 12/20/2022] Open
Abstract
INTRODUCTION Mismatch repair (MMR)-deficient and DNA polymerase epsilon (POLE)-mutated tumors exhibit a high tumor mutation burden (TMB) and have been proven to be associated with good responses to immune checkpoint inhibitor treatments. However, the relationship between mutational characteristics of MMR-deficient and POLE-mutated tumors and the spatial architecture of tumor-infiltrating lymphocytes (TILs) has not been fully evaluated. METHODS We retrieved microsatellite instability-high (MSI-high, N=20) and POLE-mutated (N=47) cases from the clinical next-generation sequencing cohort at Asan Medical Center. Whole-slide immunostaining for CD3, CD4, CD8, FoxP3 and PD-1 were performed with tissue samples of colorectal and gastric cancer (N=24) and the tumor-positive TIL cell densities were correlated with the tumor's mutational features. The findings were compared with the results of similar analyses in The Cancer Genome Atlas-Colorectal Adenocarcinoma (TCGA-COADREAD) cohort (N=592). RESULTS The MSI-high group showed significantly higher overall TMBs with a number of insertion/deletion (indel) mutations relative to the POLE-mutated group (median TMB; 83.6 vs 12.5/Mb). Oncogenic/likely-oncogenic POLE mutations were identified with ultrahypermutations (≥100 mutations/Mb) (2/47, 4.3%). Concurrent POLE mutations of unknown significance and MSI-high cases were identified in eight cases (8/67, 11%), and two of these colorectal cancers had multiple POLE mutations, showing an ultramutated phenotype (378.1 and 484.4/Mb) and low indel mutation burdens with complete loss of MSH-6 or PMS-2, which was similar to the mutational profile of the POLE-inactivated tumors. Intratumoral CD3-positive, CD4-positive, CD8-positive, FoxP3-positive and PD-1-positive TIL cell densities were more strongly correlated with the indel mutation burden than with the total TMB (correlation coefficient, 0.61-0.73 vs 0.23-0.38). In addition, PI3K/AKT/mTOR pathway mutations were commonly found in MSI-high tumors (75%) but not in POLE-mutated tumors. CONCLUSIONS Indel mutation burden rather than total TMB could serve as a predictor of high TILs in both MSI-high and POLE-mutated tumors. Multiple uncharacterized/non-pathogenic POLE mutations occurring via MMR deficiency within MSI-high tumors may have combined pathogenic roles. A mutated PI3K/AKT/mTOR pathway may be a biomarker that can be used to stratify patients with advanced MSI-high tumors for immune therapy.
Collapse
Affiliation(s)
- Hee Sang Hwang
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Deokhoon Kim
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Jene Choi
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| |
Collapse
|
|
27
|
Gebert J, Gelincik O, Oezcan-Wahlbrink M, Marshall JD, Hernandez-Sanchez A, Urban K, Long M, Cortes E, Tosti E, Katzenmaier EM, Song Y, Elsaadi A, Deng N, Vilar E, Fuchs V, Nelius N, Yuan YP, Ahadova A, Sei S, Shoemaker RH, Umar A, Wei L, Liu S, Bork P, Edelmann W, von Knebel Doeberitz M, Lipkin SM, Kloor M. Recurrent Frameshift Neoantigen Vaccine Elicits Protective Immunity With Reduced Tumor Burden and Improved Overall Survival in a Lynch Syndrome Mouse Model. Gastroenterology 2021; 161:1288-1302.e13. [PMID: 34224739 PMCID: PMC10184299 DOI: 10.1053/j.gastro.2021.06.073] [Citation(s) in RCA: 77] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2020] [Revised: 06/02/2021] [Accepted: 06/28/2021] [Indexed: 12/13/2022]
Abstract
BACKGROUND & AIMS DNA mismatch repair deficiency drives microsatellite instability (MSI). Cells with MSI accumulate numerous frameshift mutations. Frameshift mutations affecting cancer-related genes may promote tumorigenesis and, therefore, are shared among independently arising MSI tumors. Consequently, such recurrent frameshift mutations can give rise to shared immunogenic frameshift peptides (FSPs) that represent ideal candidates for a vaccine against MSI cancer. Pathogenic germline variants of mismatch repair genes cause Lynch syndrome (LS), a hereditary cancer syndrome affecting approximately 20-25 million individuals worldwide. Individuals with LS are at high risk of developing MSI cancer. Previously, we demonstrated safety and immunogenicity of an FSP-based vaccine in a phase I/IIa clinical trial in patients with a history of MSI colorectal cancer. However, the cancer-preventive effect of FSP vaccination in the scenario of LS has not yet been demonstrated. METHODS A genome-wide database of 488,235 mouse coding mononucleotide repeats was established, from which a set of candidates was selected based on repeat length, gene expression, and mutation frequency. In silico prediction, in vivo immunogenicity testing, and epitope mapping was used to identify candidates for FSP vaccination. RESULTS We identified 4 shared FSP neoantigens (Nacad [FSP-1], Maz [FSP-1], Senp6 [FSP-1], Xirp1 [FSP-1]) that induced CD4/CD8 T cell responses in naïve C57BL/6 mice. Using VCMsh2 mice, which have a conditional knockout of Msh2 in the intestinal tract and develop intestinal cancer, we showed vaccination with a combination of only 4 FSPs significantly increased FSP-specific adaptive immunity, reduced intestinal tumor burden, and prolonged overall survival. Combination of FSP vaccination with daily naproxen treatment potentiated immune response, delayed tumor growth, and prolonged survival even more effectively than FSP vaccination alone. CONCLUSIONS Our preclinical findings support a clinical strategy of recurrent FSP neoantigen vaccination for LS cancer immunoprevention.
Collapse
MESH Headings
- Adjuvants, Immunologic/pharmacology
- Animals
- Anti-Inflammatory Agents, Non-Steroidal/pharmacology
- Antigens, Neoplasm/genetics
- Antigens, Neoplasm/immunology
- Antigens, Neoplasm/pharmacology
- Cancer Vaccines/genetics
- Cancer Vaccines/immunology
- Cancer Vaccines/pharmacology
- Colorectal Neoplasms, Hereditary Nonpolyposis/drug therapy
- Colorectal Neoplasms, Hereditary Nonpolyposis/genetics
- Colorectal Neoplasms, Hereditary Nonpolyposis/immunology
- Colorectal Neoplasms, Hereditary Nonpolyposis/pathology
- Databases, Genetic
- Disease Models, Animal
- Epitopes
- Frameshift Mutation
- Immunity, Cellular/drug effects
- Immunity, Humoral/drug effects
- Immunogenetic Phenomena
- Mice, Inbred C57BL
- Mice, Knockout
- MutS Homolog 2 Protein/genetics
- Naproxen/pharmacology
- Peptide Fragments/genetics
- Peptide Fragments/immunology
- Peptide Fragments/pharmacology
- Tumor Burden/drug effects
- Tumor Microenvironment
- Vaccination
- Vaccine Efficacy
- Mice
Collapse
Affiliation(s)
- Johannes Gebert
- Department of Applied Tumor Biology, Institute of Pathology, University of Heidelberg, Heidelberg, Germany; Clinical Cooperation Unit Applied Tumor Biology, German Cancer Research Center, Heidelberg, Germany.
| | | | - Mine Oezcan-Wahlbrink
- Department of Applied Tumor Biology, Institute of Pathology, University of Heidelberg, Heidelberg, Germany; Clinical Cooperation Unit Applied Tumor Biology, German Cancer Research Center, Heidelberg, Germany
| | - Jason D Marshall
- Cancer ImmunoPrevention Laboratory, Frederick National Laboratory for Cancer Research, Frederick, Maryland
| | - Alejandro Hernandez-Sanchez
- Department of Applied Tumor Biology, Institute of Pathology, University of Heidelberg, Heidelberg, Germany; Clinical Cooperation Unit Applied Tumor Biology, German Cancer Research Center, Heidelberg, Germany
| | - Katharina Urban
- Department of Applied Tumor Biology, Institute of Pathology, University of Heidelberg, Heidelberg, Germany; Clinical Cooperation Unit Applied Tumor Biology, German Cancer Research Center, Heidelberg, Germany
| | - Mark Long
- Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, New York
| | - Eduardo Cortes
- Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, New York
| | - Elena Tosti
- Department of Cell Biology, Albert Einstein College of Medicine, New York, New York
| | - Eva-Maria Katzenmaier
- Department of Applied Tumor Biology, Institute of Pathology, University of Heidelberg, Heidelberg, Germany; Clinical Cooperation Unit Applied Tumor Biology, German Cancer Research Center, Heidelberg, Germany
| | - Yurong Song
- Cancer ImmunoPrevention Laboratory, Frederick National Laboratory for Cancer Research, Frederick, Maryland
| | - Ali Elsaadi
- Weill Cornell Medical College, New York, New York
| | - Nan Deng
- Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Eduardo Vilar
- Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Vera Fuchs
- Department of Applied Tumor Biology, Institute of Pathology, University of Heidelberg, Heidelberg, Germany; Clinical Cooperation Unit Applied Tumor Biology, German Cancer Research Center, Heidelberg, Germany
| | - Nina Nelius
- Department of Applied Tumor Biology, Institute of Pathology, University of Heidelberg, Heidelberg, Germany; Clinical Cooperation Unit Applied Tumor Biology, German Cancer Research Center, Heidelberg, Germany
| | - Yan P Yuan
- European Molecular Biology Laboratory, Structural and Computational Biology Unit, Heidelberg, Germany
| | - Aysel Ahadova
- Department of Applied Tumor Biology, Institute of Pathology, University of Heidelberg, Heidelberg, Germany; Clinical Cooperation Unit Applied Tumor Biology, German Cancer Research Center, Heidelberg, Germany
| | - Shizuko Sei
- Division of Cancer Prevention, National Cancer Institute, Bethesda, Maryland
| | - Robert H Shoemaker
- Division of Cancer Prevention, National Cancer Institute, Bethesda, Maryland
| | - Asad Umar
- Division of Cancer Prevention, National Cancer Institute, Bethesda, Maryland
| | - Lei Wei
- Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, New York
| | - Song Liu
- Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, New York
| | - Peer Bork
- European Molecular Biology Laboratory, Structural and Computational Biology Unit, Heidelberg, Germany; Max Delbrück Centre for Molecular Medicine, Berlin, Germany; Department of Bioinformatics, Biocenter, University of Würzburg, Würzburg, Germany
| | - Winfried Edelmann
- Department of Cell Biology, Albert Einstein College of Medicine, New York, New York
| | - Magnus von Knebel Doeberitz
- Department of Applied Tumor Biology, Institute of Pathology, University of Heidelberg, Heidelberg, Germany; Clinical Cooperation Unit Applied Tumor Biology, German Cancer Research Center, Heidelberg, Germany.
| | | | - Matthias Kloor
- Department of Applied Tumor Biology, Institute of Pathology, University of Heidelberg, Heidelberg, Germany; Clinical Cooperation Unit Applied Tumor Biology, German Cancer Research Center, Heidelberg, Germany.
| |
Collapse
|
|
28
|
Olkinuora AP, Peltomäki PT, Aaltonen LA, Rajamäki K. From APC to the genetics of hereditary and familial colon cancer syndromes. Hum Mol Genet 2021; 30:R206-R224. [PMID: 34329396 PMCID: PMC8490010 DOI: 10.1093/hmg/ddab208] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Revised: 07/01/2021] [Accepted: 07/05/2021] [Indexed: 11/12/2022] Open
Abstract
Hereditary colorectal cancer (CRC) syndromes attributable to high penetrance mutations represent 9-26% of young-onset CRC cases. The clinical significance of many of these mutations is understood well enough to be used in diagnostics and as an aid in patient care. However, despite the advances made in the field, a significant proportion of familial and early-onset cases remains molecularly uncharacterized and extensive work is still needed to fully understand the genetic nature of CRC susceptibility. With the emergence of next-generation sequencing and associated methods, several predisposition loci have been unraveled, but validation is incomplete. Individuals with cancer-predisposing mutations are currently enrolled in life-long surveillance, but with the development of new treatments, such as cancer vaccinations, this might change in the not so distant future for at least some individuals. For individuals without a known cause for their disease susceptibility, prevention and therapy options are less precise. Herein, we review the progress achieved in the last three decades with a focus on how CRC predisposition genes were discovered. Furthermore, we discuss the clinical implications of these discoveries and anticipate what to expect in the next decade.
Collapse
Affiliation(s)
- Alisa P Olkinuora
- Department of Medical and Clinical Genetics, Medicum, University of Helsinki, 00014 Helsinki, Finland
- iCAN Digital Precision Cancer Medicine Flagship, University of Helsinki, 00014 Helsinki, Finland
| | - Päivi T Peltomäki
- Department of Medical and Clinical Genetics, Medicum, University of Helsinki, 00014 Helsinki, Finland
- iCAN Digital Precision Cancer Medicine Flagship, University of Helsinki, 00014 Helsinki, Finland
| | - Lauri A Aaltonen
- Department of Medical and Clinical Genetics, Medicum, University of Helsinki, 00014 Helsinki, Finland
- iCAN Digital Precision Cancer Medicine Flagship, University of Helsinki, 00014 Helsinki, Finland
- Applied Tumor Genomics Research Program, Research Programs Unit, University of Helsinki, 00014 Helsinki, Finland
| | - Kristiina Rajamäki
- Department of Medical and Clinical Genetics, Medicum, University of Helsinki, 00014 Helsinki, Finland
- Applied Tumor Genomics Research Program, Research Programs Unit, University of Helsinki, 00014 Helsinki, Finland
| |
Collapse
|
|
29
|
Abstract
PURPOSE OF REVIEW Patients with Lynch syndrome have a high probability of developing colorectal and other carcinomas. This review provides a comprehensive assessment of the immunologic aspects of Lynch syndrome pathogenesis and provides an overview of potential immune interventions for patients with Lynch syndrome polyps and Lynch syndrome-associated carcinomas. RECENT FINDINGS Immunogenic properties of the majority of Lynch syndrome polyps and associated cancers include microsatellite instability leading to a high mutational burden and the development of novel frameshift peptides, i.e., neoantigens. In addition, patients with Lynch syndrome develop T cell responses in the periphery and in the tumor microenvironment (TME) to tumor-associated antigens, and a proinflammatory cytokine TME has also been identified. However, Lynch syndrome lesions also possess immunosuppressive entities such as alterations in MHC class I antigen presentation, TGFβ receptor mutations, regulatory T cells, and upregulation of PD-L1 on tumor-associated lymphocytes. The rich immune microenvironment of Lynch syndrome polyps and associated carcinomas provides an opportunity to employ the spectrum of immune-mediating agents now available to induce and enhance host immune responses and/or to also reduce immunosuppressive entities. These agents can be employed in the so-called prevention trials for the treatment of patients with Lynch syndrome polyps and for trials in patients with Lynch syndrome-associated cancers.
Collapse
Affiliation(s)
- Danielle M Pastor
- Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
- NIH Hematology Oncology Fellowship Program, National Institutes of Health, Bethesda, MD, USA
| | - Jeffrey Schlom
- Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
| |
Collapse
|
|
30
|
Matsuoka T, Yashiro M. Molecular-targeted therapy toward precision medicine for gastrointestinal cancer: Current progress and challenges. World J Gastrointest Oncol 2021; 13:366-390. [PMID: 34040699 PMCID: PMC8131909 DOI: 10.4251/wjgo.v13.i5.366] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Revised: 03/04/2021] [Accepted: 04/22/2021] [Indexed: 02/06/2023] Open
Abstract
Gastrointestinal (GI) cancer remains the deadliest cancer in the world. The current standard treatment for GI cancer focuses on 5-fluorouracil-based chemotherapeutic regimens and surgery, and molecular-targeted therapy is expected to be a more effective and less toxic therapeutic strategy for GI cancer. There is well-established evidence for the use of epidermal growth factor receptor-targeted and vascular endothelial growth factor-targeted antibodies, which should routinely be incorporated into treatment strategies for GI cancer. Other potential therapeutic targets involve the PI3K/AKT pathway, tumor growth factor-β pathway, mesenchymal-epithelial transition pathway, WNT pathway, poly (ADP-ribose) polymerase, and immune checkpoints. Many clinical trials assessing the agents of targeted therapy are underway and have presented promising and thought-provoking results. With the development of molecular biology techniques, we can identify more targetable molecular alterations in larger patient populations with GI cancer. Targeting these molecules will allow us to reach the goal of precision medicine and improve the outcomes of patients with GI cancer.
Collapse
Affiliation(s)
- Tasuku Matsuoka
- Department of Surgical Oncology, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan
| | - Masakazu Yashiro
- Department of Surgical Oncology, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan
| |
Collapse
|
|
31
|
Abidi A, Gorris MAJ, Brennan E, Jongmans MCJ, Weijers DD, Kuiper RP, de Voer RM, Hoogerbrugge N, Schreibelt G, de Vries IJM. Challenges of Neoantigen Targeting in Lynch Syndrome and Constitutional Mismatch Repair Deficiency Syndrome. Cancers (Basel) 2021; 13:2345. [PMID: 34067951 PMCID: PMC8152233 DOI: 10.3390/cancers13102345] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Revised: 04/28/2021] [Accepted: 04/30/2021] [Indexed: 12/11/2022] Open
Abstract
Lynch syndrome (LS) and constitutional mismatch repair deficiency (CMMRD) are hereditary disorders characterised by a highly increased risk of cancer development. This is due to germline aberrations in the mismatch repair (MMR) genes, which results in a high mutational load in tumours of these patients, including insertions and deletions in genes bearing microsatellites. This generates microsatellite instability and cause reading frameshifts in coding regions that could lead to the generation of neoantigens and opens up avenues for neoantigen targeting immune therapies prophylactically and therapeutically. However, major obstacles need to be overcome, such as the heterogeneity in tumour formation within and between LS and CMMRD patients, which results in considerable variability in the genes targeted by mutations, hence challenging the choice of suitable neoantigens. The machine-learning methods such as NetMHC and MHCflurry that predict neoantigen- human leukocyte antigen (HLA) binding affinity provide little information on other aspects of neoantigen presentation. Immune escape mechanisms that allow MMR-deficient cells to evade surveillance combined with the resistance to immune checkpoint therapy make the neoantigen targeting regimen challenging. Studies to delineate shared neoantigen profiles across patient cohorts, precise HLA binding algorithms, additional therapies to counter immune evasion and evaluation of biomarkers that predict the response of these patients to immune checkpoint therapy are warranted.
Collapse
Affiliation(s)
- Asima Abidi
- Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands; (A.A.); (M.A.J.G.); (E.B.); (G.S.)
| | - Mark A. J. Gorris
- Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands; (A.A.); (M.A.J.G.); (E.B.); (G.S.)
| | - Evan Brennan
- Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands; (A.A.); (M.A.J.G.); (E.B.); (G.S.)
| | - Marjolijn C. J. Jongmans
- Princess Máxima Center for Pediatric Oncology, 3584 CS Utrecht, The Netherlands; (M.C.J.J.); (D.D.W.); (R.P.K.)
- Department of Genetics, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands
| | - Dilys D. Weijers
- Princess Máxima Center for Pediatric Oncology, 3584 CS Utrecht, The Netherlands; (M.C.J.J.); (D.D.W.); (R.P.K.)
| | - Roland P. Kuiper
- Princess Máxima Center for Pediatric Oncology, 3584 CS Utrecht, The Netherlands; (M.C.J.J.); (D.D.W.); (R.P.K.)
- Department of Genetics, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands
| | - Richarda M. de Voer
- Department of Human Genetics, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands; (R.M.d.V.); (N.H.)
| | - Nicoline Hoogerbrugge
- Department of Human Genetics, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands; (R.M.d.V.); (N.H.)
| | - Gerty Schreibelt
- Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands; (A.A.); (M.A.J.G.); (E.B.); (G.S.)
| | - I. Jolanda M. de Vries
- Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands; (A.A.); (M.A.J.G.); (E.B.); (G.S.)
- Department of Medical Oncology, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands
| |
Collapse
|
|
32
|
Sherman WJ, Vitaz TW. Nivolumab with radiation therapy in a glioblastoma patient with Lynch syndrome. BMJ Case Rep 2021; 14:14/4/e241026. [PMID: 33906875 PMCID: PMC8088241 DOI: 10.1136/bcr-2020-241026] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Lynch syndrome is an autosomal dominant disorder leading to cancer predisposition caused by mutations in mismatch repair genes. There is minimal published experience treating glioblastoma in patients with Lynch syndrome. We report a patient with Lynch syndrome who was initially diagnosed with a left occipital isocitrate dehydrogenase (IDH) wild-type glioblastoma. After resection, she was treated with chemoradiation, followed by tumour treating fields. Three years after diagnosis, recurrence was resected. After refusing cytotoxic chemotherapy, decision was made to treat with off-label nivolumab concurrently with radiation. She has been maintained on nivolumab without recurrence of her glioblastoma now over 5 years out from her initial diagnosis. This case provides the first report of glioblastoma in a patient with Lynch syndrome responding to nivolumab and concurrent radiation. In patients with Lynch syndrome and glioblastoma, immunotherapy in the form of nivolumab may be an alternative option to standard cytotoxic chemotherapy.
Collapse
Affiliation(s)
- Wendy Joyce Sherman
- Department of Neurology and Neurosurgery, Mayo Clinic, Jacksonville, FL, USA
| | - Todd W Vitaz
- Department of Neurosurgery, Spectrum Health, Grand Rapids, MI, USA
| |
Collapse
|
|
33
|
Becker JP, Helm D, Rettel M, Stein F, Hernandez-Sanchez A, Urban K, Gebert J, Kloor M, Neu-Yilik G, von Knebel Doeberitz M, Hentze MW, Kulozik AE. NMD inhibition by 5-azacytidine augments presentation of immunogenic frameshift-derived neoepitopes. iScience 2021; 24:102389. [PMID: 33981976 PMCID: PMC8082087 DOI: 10.1016/j.isci.2021.102389] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2021] [Revised: 03/11/2021] [Accepted: 03/30/2021] [Indexed: 12/22/2022] Open
Abstract
Frameshifted protein sequences elicit tumor-specific T cell-mediated immune responses in microsatellite-unstable (MSI) cancers if presented by HLA class I molecules. However, their expression and presentation are limited by nonsense-mediated RNA decay (NMD). We employed an unbiased immunopeptidomics workflow to analyze MSI HCT-116 cells and identified >10,000 HLA class I-presented peptides including five frameshift-derived InDel neoepitopes. Notably, pharmacological NMD inhibition with 5-azacytidine stabilizes frameshift-bearing transcripts and increases the HLA class I-mediated presentation of InDel neoepitopes. The frameshift mutation underlying one of the identified InDel neoepitopes is highly recurrent in MSI colorectal cancer cell lines and primary patient samples, and immunization with the corresponding neoepitope induces strong CD8+ T cell responses in an HLA-A∗02:01 transgenic mouse model. Our data show directly that pharmacological NMD inhibition augments HLA class I-mediated presentation of immunogenic frameshift-derived InDel neoepitopes thus highlighting the clinical potential of NMD inhibition in anti-cancer immunotherapy strategies.
Collapse
Affiliation(s)
- Jonas P. Becker
- Molecular Medicine Partnership Unit (MMPU), Heidelberg University, 69120 Heidelberg, Germany
- European Molecular Biology Laboratory (EMBL), 69117 Heidelberg, Germany
- Department of Pediatric Oncology, Hematology and Immunology, Heidelberg University, 69120 Heidelberg, Germany
- Hopp Children's Cancer Center, National Center for Tumor Diseases (NCT), 69120 Heidelberg, Germany
| | - Dominic Helm
- Genomics and Proteomics Core Facility, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
| | - Mandy Rettel
- European Molecular Biology Laboratory (EMBL), 69117 Heidelberg, Germany
| | - Frank Stein
- European Molecular Biology Laboratory (EMBL), 69117 Heidelberg, Germany
| | - Alejandro Hernandez-Sanchez
- Molecular Medicine Partnership Unit (MMPU), Heidelberg University, 69120 Heidelberg, Germany
- European Molecular Biology Laboratory (EMBL), 69117 Heidelberg, Germany
- Department of Applied Tumor Biology, Institute of Pathology, Heidelberg University, 69120 Heidelberg, Germany
- Collaboration Unit Applied Tumor Biology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
| | - Katharina Urban
- Molecular Medicine Partnership Unit (MMPU), Heidelberg University, 69120 Heidelberg, Germany
- European Molecular Biology Laboratory (EMBL), 69117 Heidelberg, Germany
- Department of Applied Tumor Biology, Institute of Pathology, Heidelberg University, 69120 Heidelberg, Germany
- Collaboration Unit Applied Tumor Biology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
| | - Johannes Gebert
- Molecular Medicine Partnership Unit (MMPU), Heidelberg University, 69120 Heidelberg, Germany
- European Molecular Biology Laboratory (EMBL), 69117 Heidelberg, Germany
- Department of Applied Tumor Biology, Institute of Pathology, Heidelberg University, 69120 Heidelberg, Germany
- Collaboration Unit Applied Tumor Biology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
| | - Matthias Kloor
- Molecular Medicine Partnership Unit (MMPU), Heidelberg University, 69120 Heidelberg, Germany
- European Molecular Biology Laboratory (EMBL), 69117 Heidelberg, Germany
- Department of Applied Tumor Biology, Institute of Pathology, Heidelberg University, 69120 Heidelberg, Germany
- Collaboration Unit Applied Tumor Biology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
| | - Gabriele Neu-Yilik
- Molecular Medicine Partnership Unit (MMPU), Heidelberg University, 69120 Heidelberg, Germany
- European Molecular Biology Laboratory (EMBL), 69117 Heidelberg, Germany
- Department of Pediatric Oncology, Hematology and Immunology, Heidelberg University, 69120 Heidelberg, Germany
- Hopp Children's Cancer Center, National Center for Tumor Diseases (NCT), 69120 Heidelberg, Germany
| | - Magnus von Knebel Doeberitz
- Molecular Medicine Partnership Unit (MMPU), Heidelberg University, 69120 Heidelberg, Germany
- European Molecular Biology Laboratory (EMBL), 69117 Heidelberg, Germany
- Department of Applied Tumor Biology, Institute of Pathology, Heidelberg University, 69120 Heidelberg, Germany
- Collaboration Unit Applied Tumor Biology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
| | - Matthias W. Hentze
- Molecular Medicine Partnership Unit (MMPU), Heidelberg University, 69120 Heidelberg, Germany
- European Molecular Biology Laboratory (EMBL), 69117 Heidelberg, Germany
| | - Andreas E. Kulozik
- Molecular Medicine Partnership Unit (MMPU), Heidelberg University, 69120 Heidelberg, Germany
- European Molecular Biology Laboratory (EMBL), 69117 Heidelberg, Germany
- Department of Pediatric Oncology, Hematology and Immunology, Heidelberg University, 69120 Heidelberg, Germany
- Hopp Children's Cancer Center, National Center for Tumor Diseases (NCT), 69120 Heidelberg, Germany
| |
Collapse
|
|
34
|
Sui Q, Liu D, Jiang W, Tang J, Kong L, Han K, Liao L, Li Y, Ou Q, Xiao B, Liu G, Ling Y, Chen J, Liu Z, Zuo Z, Pan Z, Zhou P, Zheng J, Ding PR. Dickkopf 1 impairs the tumor response to PD-1 blockade by inactivating CD8+ T cells in deficient mismatch repair colorectal cancer. J Immunother Cancer 2021; 9:e001498. [PMID: 33782107 PMCID: PMC8009229 DOI: 10.1136/jitc-2020-001498] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/08/2021] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND Dickkopf 1 (DKK1) is associated with tumor progression. However, whether DKK1 influences the tumor response to programmed cell death protein 1 (PD-1) blockade in colorectal cancers (CRCs) with deficient mismatch repair (dMMR) or microsatellite instability (MSI) has never been clarified. METHODS Tumor tissues from 80 patients with dMMR CRC were evaluated for DKK1 expression and immune status via immunohistochemistry. Serum DKK1 was measured in another set of 43 patients who received PD-1 blockade therapy. CT26 cells and dMMR CRC organoids were cocultured with T cells, and CT26-grafted BALB/c mice were also constructed. T-cell cytotoxicity was assessed by apoptosis assays and flow cytometry. The pathway through which DKK1 regulates CD8+ T cells was investigated using RNA sequencing, and chromatin immunoprecipitation and luciferase reporter assays were conducted to determine the downstream transcription factors of DKK1. RESULTS Elevated DKK1 expression was associated with recurrence and decreased CD8+ T-cell infiltration in dMMR CRCs, and patients with high-serum DKK1 had a poor response to PD-1 blockade. RNA interference or neutralization of DKK1 in CRC cells enhanced CD8+ T-cell cytotoxicity, while DKK1 decreased T-bet expression and activated GSK3β in CD8+ T cells. In addition, E2F1, a downstream transcription factor of GSK3β, directly upregulated T-bet expression. In organoid models, the proportion of apoptotic cells was elevated after individual neutralization of PD-1 or DKK1 and was further increased on combined neutralization of PD-1 and DKK1. CONCLUSIONS DKK1 suppressed the antitumor immune reaction through the GSK3β/E2F1/T-bet axis in CD8+ T cells. Elevated serum DKK1 predicted poor tumor response to PD-1 blockade in dMMR/MSI CRCs, and DKK1 neutralization may restore sensitivity to PD-1 blockade.
Collapse
Affiliation(s)
- Qiaoqi Sui
- Department of Colorectal Surgery, Sun Yat-sen University Cancer Center, Guangzhou, China
- State Key Laboratory of Oncology in South China, Guangzhou, China
- Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Dingxin Liu
- State Key Laboratory of Oncology in South China, Guangzhou, China
- Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
- Department of Experimental Research, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Wu Jiang
- Department of Colorectal Surgery, Sun Yat-sen University Cancer Center, Guangzhou, China
- State Key Laboratory of Oncology in South China, Guangzhou, China
- Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Jinghua Tang
- Department of Colorectal Surgery, Sun Yat-sen University Cancer Center, Guangzhou, China
- State Key Laboratory of Oncology in South China, Guangzhou, China
- Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Lingheng Kong
- Department of Colorectal Surgery, Sun Yat-sen University Cancer Center, Guangzhou, China
- State Key Laboratory of Oncology in South China, Guangzhou, China
- Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Kai Han
- Department of Colorectal Surgery, Sun Yat-sen University Cancer Center, Guangzhou, China
- State Key Laboratory of Oncology in South China, Guangzhou, China
- Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Leen Liao
- Department of Colorectal Surgery, Sun Yat-sen University Cancer Center, Guangzhou, China
- State Key Laboratory of Oncology in South China, Guangzhou, China
- Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Yuan Li
- Department of Colorectal Surgery, Sun Yat-sen University Cancer Center, Guangzhou, China
- State Key Laboratory of Oncology in South China, Guangzhou, China
- Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Qingjian Ou
- Department of Colorectal Surgery, Sun Yat-sen University Cancer Center, Guangzhou, China
- State Key Laboratory of Oncology in South China, Guangzhou, China
- Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
- Department of Experimental Research, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Binyi Xiao
- Department of Colorectal Surgery, Sun Yat-sen University Cancer Center, Guangzhou, China
- State Key Laboratory of Oncology in South China, Guangzhou, China
- Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Guochen Liu
- State Key Laboratory of Oncology in South China, Guangzhou, China
- Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
- Department of Gynecologic Oncology, Sun Yat-sen University Cancer Center, , Guangzhou, China
| | - Yihong Ling
- State Key Laboratory of Oncology in South China, Guangzhou, China
- Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
- Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Jiewei Chen
- State Key Laboratory of Oncology in South China, Guangzhou, China
- Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
- Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Zexian Liu
- State Key Laboratory of Oncology in South China, Guangzhou, China
- Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
- Department of Experimental Research, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Zhixiang Zuo
- State Key Laboratory of Oncology in South China, Guangzhou, China
- Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
- Department of Experimental Research, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Zhizhong Pan
- Department of Colorectal Surgery, Sun Yat-sen University Cancer Center, Guangzhou, China
- State Key Laboratory of Oncology in South China, Guangzhou, China
- Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Penghui Zhou
- State Key Laboratory of Oncology in South China, Guangzhou, China
- Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
- Department of Experimental Research, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Jian Zheng
- State Key Laboratory of Oncology in South China, Guangzhou, China
- Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
- Department of Experimental Research, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Pei-Rong Ding
- Department of Colorectal Surgery, Sun Yat-sen University Cancer Center, Guangzhou, China
- State Key Laboratory of Oncology in South China, Guangzhou, China
- Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| |
Collapse
|
|
35
|
Keshavarz-Fathi M, Rezaei N. Cancer Immunoprevention: Current Status and Future Directions. Arch Immunol Ther Exp (Warsz) 2021; 69:3. [PMID: 33638703 DOI: 10.1007/s00005-021-00604-x] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2019] [Accepted: 02/06/2021] [Indexed: 12/24/2022]
Abstract
Cancer is one of the most serious diseases affecting health and the second leading cause of death worldwide. Despite the development of various therapeutic modalities to deal with cancer, limited improvement in overall survival of patients has been yielded. Since there is no certain cure for cancer, detection of premalignant lesions, and prevention of their progression are vital to the decline of high morbidity and mortality of cancer. Among approaches to cancer prevention, immunoprevention has gained further attention in recent years. Deep understanding of the tumor/immune system interplay and successful prevention of virally-induced malignancies by vaccines have paved the way toward broadening cancer immunoprevention application. The identification of tumor antigens in premalignant lesions was the turning point in cancer immunoprevention that led to designing preventive vaccines for various malignancies including multiple myeloma, colorectal, and breast cancer. In addition to vaccines, immune checkpoint inhibitors are also being tested for the prevention of oral squamous cell carcinoma (SCC), and imiquimod which is an established drug for the prevention of skin SCC, is a non-specific immunomodulator. Herein, to provide a bench-to-bedside understanding of cancer immunoprevention, we will review the role of the immune system in suppression and promotion of tumors, immunoprevention of virally-induced cancers, identification of tumor antigens in premalignant lesions, and clinical advances of cancer immunoprevention.
Collapse
Affiliation(s)
- Mahsa Keshavarz-Fathi
- School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
- Cancer Immunology Project (CIP), Universal Scientific Education and Research Network (USERN), Tehran, Iran.
- Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Dr. Qarib St, Keshavarz Blvd, 14194, Tehran, Iran.
| | - Nima Rezaei
- Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Dr. Qarib St, Keshavarz Blvd, 14194, Tehran, Iran.
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
- Cancer Immunology Project (CIP), Universal Scientific Education and Research Network (USERN), Stockholm, Sweden.
| |
Collapse
|
|
36
|
Laghi L, Negri F, Gaiani F, Cavalleri T, Grizzi F, de’ Angelis GL, Malesci A. Prognostic and Predictive Cross-Roads of Microsatellite Instability and Immune Response to Colon Cancer. Int J Mol Sci 2020; 21:9680. [PMID: 33353162 PMCID: PMC7766746 DOI: 10.3390/ijms21249680] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Revised: 12/14/2020] [Accepted: 12/15/2020] [Indexed: 12/21/2022] Open
Abstract
Understanding molecular features of colon cancer has shed light on its pathogenesis and progression. Over time, some of these features acquired clinical dignity and were incorporated in decision making. Namely, microsatellite instability (MSI) due to mismatch repair of defects, which primarily was adopted for the diagnosis of Lynch syndrome, became recognized as the biomarker of a different disease type, showing a less aggressive behavior. MSI tumors harbor high amounts of tumor infiltrating lymphocytes (TILs) due to their peculiar load in neoantigens. However, microsatellite stable colon cancer may also show high amounts of TILs, and this feature is as well associated with better outcomes. High TIL loads are in general associated with a favorable prognosis, especially in stage II colon cancer, and therein identifies a patient subset with the lowest probability of relapse. With respect to post-surgical adjuvant treatment, particularly in stage III, TILs predictive ability seems to weaken along with the progression of the disease, being less evident in high risk patients. Moving from cohort studies to the analysis of a series from clinical trials contributed to increase the robustness of TILs as a biomarker. The employment of high TIL densities as an indicator of good prognosis in early-stage colon cancers is strongly advisable, while in late-stage colon cancers the employment as an indicator of good responsiveness to post-surgical therapy requires refinement. It remains to be clarified whether TILs could help in identifying those patients with node-positive cancers to whom adjuvant treatment could be spared, at least in low-risk groups as defined by the TNM staging system.
Collapse
Affiliation(s)
- Luigi Laghi
- Department of Medicine and Surgery, University of Parma, 43121 Parma, Italy; (F.G.); (G.L.d.A.)
- Laboratory of Molecular Gastroenterology, Humanitas Clinical and Research Center IRCCS, Rozzano, 20089 Milan, Italy;
| | - Francesca Negri
- Medical Oncology Unit, University Hospital of Parma, 43121 Parma, Italy;
| | - Federica Gaiani
- Department of Medicine and Surgery, University of Parma, 43121 Parma, Italy; (F.G.); (G.L.d.A.)
| | - Tommaso Cavalleri
- Laboratory of Molecular Gastroenterology, Humanitas Clinical and Research Center IRCCS, Rozzano, 20089 Milan, Italy;
| | - Fabio Grizzi
- Department of Immunology and Inflammation, Humanitas Clinical and Research Center IRCCS, Rozzano, 20089 Milan, Italy;
| | - Gian Luigi de’ Angelis
- Department of Medicine and Surgery, University of Parma, 43121 Parma, Italy; (F.G.); (G.L.d.A.)
| | - Alberto Malesci
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, 20090 Milan, Italy;
- Department of Gastroenterology, Humanitas Clinical and Research Center IRCCS, Rozzano, 20089 Milan, Italy
| |
Collapse
|
|
37
|
Feng M, Zhao Z, Yang M, Ji J, Zhu D. T-cell-based immunotherapy in colorectal cancer. Cancer Lett 2020; 498:201-209. [PMID: 33129958 DOI: 10.1016/j.canlet.2020.10.040] [Citation(s) in RCA: 53] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2020] [Revised: 09/08/2020] [Accepted: 10/21/2020] [Indexed: 02/06/2023]
Abstract
Colorectal cancer (CRC) is the leading cause of cancer death worldwide. CRC therapeutic strategies include surgical resection, chemotherapy, radiotherapy, and other approaches. However, patients with metastatic CRC have worse prognoses. In recent years, T-cell-based immunotherapy has elicited promising responses in B-cell malignancies, melanoma, and lung cancer, but most CRC patients are resistant to immunotherapy, chemotherapy, and targeted therapy. Immune checkpoint inhibitors have shown encouraging results in non-small cell lung cancer, melanoma, and other cancers, but immune checkpoint blockade is only effective for CRC subset with microsatellite instability. Other immunotherapies, such as cytokines, cancer vaccines, small molecules, oncolytic viruses, and chimeric antigen-receptor therapy, are currently in use against CRC. This review analyzes recent developments in immunotherapy for CRC treatment as well as the challenges in overcoming resistance.
Collapse
Affiliation(s)
- Mei Feng
- Minhang Hospital and Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, 201203, China
| | - Zhongwei Zhao
- Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Affiliated Lishui Hospital of Zhejiang University, Lishui, 323000, China
| | - Mengxuan Yang
- Minhang Hospital and Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, 201203, China
| | - Jiansong Ji
- Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Affiliated Lishui Hospital of Zhejiang University, Lishui, 323000, China.
| | - Di Zhu
- Minhang Hospital and Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, 201203, China; Key Laboratory of Smart Drug Delivery, Ministry of Education, & State Key Laboratory of Molecular Engineering of Polymers, School of Pharmacy, Fudan University, Shanghai, 201203, China; Shanghai Engineering Research Center of ImmunoTherapeutics, Fudan University, 201203, China.
| |
Collapse
|
|
38
|
DiNatale RG, Hakimi AA, Chan TA. Genomics-based immuno-oncology: bridging the gap between immunology and tumor biology. Hum Mol Genet 2020; 29:R214-R225. [PMID: 33029628 PMCID: PMC7574960 DOI: 10.1093/hmg/ddaa203] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2020] [Revised: 09/05/2020] [Accepted: 09/08/2020] [Indexed: 12/14/2022] Open
Abstract
The first hypotheses about how the immune system affects cancers were proposed in the early 20th century. These early concepts about cancer immunosurveillance were further developed in the decades that followed, but a detailed understanding of cancer immunity remained elusive. It was only recently, through the advent of high-throughput technologies, that scientists gained the ability to profile tumors with a resolution that allowed for granular assessment of both tumor cells and the tumor microenvironment. The advent of immune checkpoint inhibitors (ICIs), which have proven to be effective cancer therapies in many malignancies, has spawned great interest in developing biomarkers for efficacy, an endeavor that highlighted the value of dissecting tumor immunity using large-scale methods. Response to ICI therapy has been shown to be a highly complex process, where the dynamics of tumor and immune cells is key to success. The need to understand the biologic mechanisms at the tumor-immune interface has given rise to the field of cancer immunogenomics, a discipline that aims to bridge the gap between cancer genomics and classical immunology. We provide a broad overview of this emerging branch of translational science, summarizing common platforms used and recent discoveries in the field, which are having direct clinical implications. Our discussion will be centered around the genetic foundations governing tumor immunity and molecular determinants associated with clinical benefit from ICI therapy. We emphasize the importance of molecular diversity as a driver of anti-tumor immunity and discuss how these factors can be probed using genomic approaches.
Collapse
Affiliation(s)
- Renzo G DiNatale
- Immunogenomics and Precision Oncology Platform, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
- Urology Department, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - A Ari Hakimi
- Urology Department, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Timothy A Chan
- Immunogenomics and Precision Oncology Platform, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
- Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
- Center for Immunotherapy and Precision Immuno-Oncology, Cleveland Clinic, Cleveland, OH 44195, USA
- Lerner Research Institute and Taussig Cancer Center, Cleveland Clinic, Cleveland, OH 44195, USA
| |
Collapse
|
|
39
|
Leko V, Rosenberg SA. Identifying and Targeting Human Tumor Antigens for T Cell-Based Immunotherapy of Solid Tumors. Cancer Cell 2020; 38:454-472. [PMID: 32822573 PMCID: PMC7737225 DOI: 10.1016/j.ccell.2020.07.013] [Citation(s) in RCA: 275] [Impact Index Per Article: 55.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2020] [Revised: 07/24/2020] [Accepted: 07/29/2020] [Indexed: 12/20/2022]
Abstract
Cancer elimination in humans can be achieved with immunotherapy that relies on T lymphocyte-mediated recognition of tumor antigens. Several types of these antigens have been recognized based on their cellular origins and expression patterns, while their detection has been greatly facilitated by recent achievements in next-generation sequencing and immunopeptidomics. Some of them have been targeted in clinical trials with various immunotherapy approaches, while many others remain untested. Here, we discuss molecular identification of different tumor antigen types, and the clinical safety and efficacy of targeting them with immunotherapy. Additionally, we suggest strategies to increase the efficacy and availability of antigen-directed immunotherapies for treatment of patients with metastatic cancer.
Collapse
Affiliation(s)
- Vid Leko
- Surgery Branch, National Cancer Institute, National Institutes of Health, Building 10-CRC, Room 3-3942, 10 Center Drive, Bethesda, MD 20892, USA.
| | - Steven A Rosenberg
- Surgery Branch, National Cancer Institute, National Institutes of Health, Building 10-CRC, Room 3-3942, 10 Center Drive, Bethesda, MD 20892, USA.
| |
Collapse
|
|
40
|
Ballhausen A, Przybilla MJ, Jendrusch M, Haupt S, Pfaffendorf E, Seidler F, Witt J, Hernandez Sanchez A, Urban K, Draxlbauer M, Krausert S, Ahadova A, Kalteis MS, Pfuderer PL, Heid D, Stichel D, Gebert J, Bonsack M, Schott S, Bläker H, Seppälä T, Mecklin JP, Ten Broeke S, Nielsen M, Heuveline V, Krzykalla J, Benner A, Riemer AB, von Knebel Doeberitz M, Kloor M. The shared frameshift mutation landscape of microsatellite-unstable cancers suggests immunoediting during tumor evolution. Nat Commun 2020; 11:4740. [PMID: 32958755 PMCID: PMC7506541 DOI: 10.1038/s41467-020-18514-5] [Citation(s) in RCA: 87] [Impact Index Per Article: 17.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2019] [Accepted: 08/21/2020] [Indexed: 02/06/2023] Open
Abstract
The immune system can recognize and attack cancer cells, especially those with a high load of mutation-induced neoantigens. Such neoantigens are abundant in DNA mismatch repair (MMR)-deficient, microsatellite-unstable (MSI) cancers. MMR deficiency leads to insertion/deletion (indel) mutations at coding microsatellites (cMS) and to neoantigen-inducing translational frameshifts. Here, we develop a tool to quantify frameshift mutations in MSI colorectal and endometrial cancer. Our results show that frameshift mutation frequency is negatively correlated to the predicted immunogenicity of the resulting peptides, suggesting counterselection of cell clones with highly immunogenic frameshift peptides. This correlation is absent in tumors with Beta-2-microglobulin mutations, and HLA-A*02:01 status is related to cMS mutation patterns. Importantly, certain outlier mutations are common in MSI cancers despite being related to frameshift peptides with functionally confirmed immunogenicity, suggesting a possible driver role during MSI tumor evolution. Neoantigens resulting from shared mutations represent promising vaccine candidates for prevention of MSI cancers.
Collapse
Affiliation(s)
- Alexej Ballhausen
- Department of Applied Tumor Biology, Institute of Pathology, University of Heidelberg, Heidelberg, Germany
- Collaboration Unit Applied Tumor Biology, German Cancer Research Center (DKFZ), Heidelberg, Germany
- Molecular Medicine Partnership Unit (MMPU), Heidelberg University Hospital and EMBL, Heidelberg, Germany
| | - Moritz Jakob Przybilla
- Department of Applied Tumor Biology, Institute of Pathology, University of Heidelberg, Heidelberg, Germany
- Collaboration Unit Applied Tumor Biology, German Cancer Research Center (DKFZ), Heidelberg, Germany
- Molecular Medicine Partnership Unit (MMPU), Heidelberg University Hospital and EMBL, Heidelberg, Germany
| | - Michael Jendrusch
- Department of Applied Tumor Biology, Institute of Pathology, University of Heidelberg, Heidelberg, Germany
- Collaboration Unit Applied Tumor Biology, German Cancer Research Center (DKFZ), Heidelberg, Germany
- Molecular Medicine Partnership Unit (MMPU), Heidelberg University Hospital and EMBL, Heidelberg, Germany
| | - Saskia Haupt
- Engineering Mathematics and Computing Lab (EMCL), Interdisciplinary Center for Scientific Computing (IWR), Heidelberg University, Heidelberg, Germany
| | - Elisabeth Pfaffendorf
- Department of Applied Tumor Biology, Institute of Pathology, University of Heidelberg, Heidelberg, Germany
- Collaboration Unit Applied Tumor Biology, German Cancer Research Center (DKFZ), Heidelberg, Germany
- Molecular Medicine Partnership Unit (MMPU), Heidelberg University Hospital and EMBL, Heidelberg, Germany
| | - Florian Seidler
- Department of Applied Tumor Biology, Institute of Pathology, University of Heidelberg, Heidelberg, Germany
- Collaboration Unit Applied Tumor Biology, German Cancer Research Center (DKFZ), Heidelberg, Germany
- Molecular Medicine Partnership Unit (MMPU), Heidelberg University Hospital and EMBL, Heidelberg, Germany
| | - Johannes Witt
- Department of Applied Tumor Biology, Institute of Pathology, University of Heidelberg, Heidelberg, Germany
- Collaboration Unit Applied Tumor Biology, German Cancer Research Center (DKFZ), Heidelberg, Germany
- Molecular Medicine Partnership Unit (MMPU), Heidelberg University Hospital and EMBL, Heidelberg, Germany
| | - Alejandro Hernandez Sanchez
- Department of Applied Tumor Biology, Institute of Pathology, University of Heidelberg, Heidelberg, Germany
- Collaboration Unit Applied Tumor Biology, German Cancer Research Center (DKFZ), Heidelberg, Germany
- Molecular Medicine Partnership Unit (MMPU), Heidelberg University Hospital and EMBL, Heidelberg, Germany
| | - Katharina Urban
- Department of Applied Tumor Biology, Institute of Pathology, University of Heidelberg, Heidelberg, Germany
- Collaboration Unit Applied Tumor Biology, German Cancer Research Center (DKFZ), Heidelberg, Germany
- Molecular Medicine Partnership Unit (MMPU), Heidelberg University Hospital and EMBL, Heidelberg, Germany
| | - Markus Draxlbauer
- Department of Applied Tumor Biology, Institute of Pathology, University of Heidelberg, Heidelberg, Germany
- Collaboration Unit Applied Tumor Biology, German Cancer Research Center (DKFZ), Heidelberg, Germany
- Molecular Medicine Partnership Unit (MMPU), Heidelberg University Hospital and EMBL, Heidelberg, Germany
| | - Sonja Krausert
- Department of Applied Tumor Biology, Institute of Pathology, University of Heidelberg, Heidelberg, Germany
- Collaboration Unit Applied Tumor Biology, German Cancer Research Center (DKFZ), Heidelberg, Germany
- Molecular Medicine Partnership Unit (MMPU), Heidelberg University Hospital and EMBL, Heidelberg, Germany
| | - Aysel Ahadova
- Department of Applied Tumor Biology, Institute of Pathology, University of Heidelberg, Heidelberg, Germany
- Collaboration Unit Applied Tumor Biology, German Cancer Research Center (DKFZ), Heidelberg, Germany
- Molecular Medicine Partnership Unit (MMPU), Heidelberg University Hospital and EMBL, Heidelberg, Germany
| | - Martin Simon Kalteis
- Department of Applied Tumor Biology, Institute of Pathology, University of Heidelberg, Heidelberg, Germany
- Collaboration Unit Applied Tumor Biology, German Cancer Research Center (DKFZ), Heidelberg, Germany
- Molecular Medicine Partnership Unit (MMPU), Heidelberg University Hospital and EMBL, Heidelberg, Germany
| | - Pauline L Pfuderer
- Department of Applied Tumor Biology, Institute of Pathology, University of Heidelberg, Heidelberg, Germany
- Collaboration Unit Applied Tumor Biology, German Cancer Research Center (DKFZ), Heidelberg, Germany
- Molecular Medicine Partnership Unit (MMPU), Heidelberg University Hospital and EMBL, Heidelberg, Germany
| | - Daniel Heid
- Department of Applied Tumor Biology, Institute of Pathology, University of Heidelberg, Heidelberg, Germany
- Collaboration Unit Applied Tumor Biology, German Cancer Research Center (DKFZ), Heidelberg, Germany
- Molecular Medicine Partnership Unit (MMPU), Heidelberg University Hospital and EMBL, Heidelberg, Germany
| | - Damian Stichel
- Department of Applied Tumor Biology, Institute of Pathology, University of Heidelberg, Heidelberg, Germany
- Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Johannes Gebert
- Department of Applied Tumor Biology, Institute of Pathology, University of Heidelberg, Heidelberg, Germany
- Collaboration Unit Applied Tumor Biology, German Cancer Research Center (DKFZ), Heidelberg, Germany
- Molecular Medicine Partnership Unit (MMPU), Heidelberg University Hospital and EMBL, Heidelberg, Germany
| | - Maria Bonsack
- Immunotherapy and Immunoprevention, German Cancer Research Center (DKFZ), Heidelberg, Germany
- Molecular Vaccine Design, German Center for Infection Research (DZIF), partner site Heidelberg, Heidelberg, Germany
- Faculty of Biosciences, Heidelberg University, Heidelberg, Germany
| | - Sarah Schott
- Department of Obstetrics and Gynecology, University Hospital Heidelberg, Heidelberg, Germany
| | - Hendrik Bläker
- Institute of Pathology, University Hospital Leipzig, Leipzig, Germany
| | - Toni Seppälä
- Department of Gastrointestinal Surgery, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
| | - Jukka-Pekka Mecklin
- Department of Education and Research, Central Finland Central Hospital, Jyväskylä, Finland
- Department of Sports and Health Sciences, University of Jyväskylä, Jyväskylä, Finland
| | - Sanne Ten Broeke
- Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands
| | - Maartje Nielsen
- Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands
| | - Vincent Heuveline
- Engineering Mathematics and Computing Lab (EMCL), Interdisciplinary Center for Scientific Computing (IWR), Heidelberg University, Heidelberg, Germany
| | - Julia Krzykalla
- Division of Biostatistics, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Axel Benner
- Division of Biostatistics, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Angelika Beate Riemer
- Immunotherapy and Immunoprevention, German Cancer Research Center (DKFZ), Heidelberg, Germany
- Molecular Vaccine Design, German Center for Infection Research (DZIF), partner site Heidelberg, Heidelberg, Germany
| | - Magnus von Knebel Doeberitz
- Department of Applied Tumor Biology, Institute of Pathology, University of Heidelberg, Heidelberg, Germany
- Collaboration Unit Applied Tumor Biology, German Cancer Research Center (DKFZ), Heidelberg, Germany
- Molecular Medicine Partnership Unit (MMPU), Heidelberg University Hospital and EMBL, Heidelberg, Germany
| | - Matthias Kloor
- Department of Applied Tumor Biology, Institute of Pathology, University of Heidelberg, Heidelberg, Germany.
- Collaboration Unit Applied Tumor Biology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
- Molecular Medicine Partnership Unit (MMPU), Heidelberg University Hospital and EMBL, Heidelberg, Germany.
| |
Collapse
|
|
41
|
Wang F, Long J, Li L, Zhao ZB, Wei F, Yao Y, Qiu WJ, Wu ZX, Luo QQ, Liu W, Quan YB, Lian ZX, Cao J. Mutations in the notch signalling pathway are associated with enhanced anti-tumour immunity in colorectal cancer. J Cell Mol Med 2020; 24:12176-12187. [PMID: 32924269 PMCID: PMC7579712 DOI: 10.1111/jcmm.15867] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2020] [Revised: 08/20/2020] [Accepted: 08/25/2020] [Indexed: 12/24/2022] Open
Abstract
The Notch signalling pathway is involved in the development of several cancers, including colorectal cancer (CRC). However, whether mutations in this pathway could alter the CRC immunophenotype remains unknown. Here, we investigated the relationship between Notch signalling pathway mutations and the tumour immune microenvironment by analysing gene expression data from the GSE108989 single T cell RNA sequencing data set and The Cancer Genome Atlas (TCGA) data set. We found that Notch signalling pathway mutations were associated with an increased number of tumour-specific CD8+ T cells and decreased number of inhibitory regulatory T (Treg) cells, representing an enhanced anti-tumour response in the GSE108989 data set. In TCGA data set, we also found that Notch signalling pathway mutations were associated with enrichment of genes associated with immune activation pathways and higher expressions of PDCD1, GZMB and PRF1. Although Notch signalling pathway mutations did not affect the overall survival and disease-free survival of CRC patients, they were associated with earlier disease stages and lower rates of metastasis. These results demonstrated that Notch signalling pathway mutations can enhance anti-tumour immunity in CRC, as validated by the two data sets, suggesting that they may be promising biomarkers for immune checkpoint blockade therapies for CRC patients.
Collapse
Affiliation(s)
- Fei Wang
- Department of General Surgery, Guangzhou Digestive Disease Center, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, Guangdong, China
| | - Jie Long
- Department of General Surgery, Guangzhou Digestive Disease Center, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, Guangdong, China.,Chronic Disease Laboratory, Institutes for Life Sciences, South China University of Technology, Guangzhou, China.,Institute of Immunology and School of Life Sciences, University of Science and Technology of China, Hefei, China
| | - Liang Li
- Department of General Surgery, Guangzhou Digestive Disease Center, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, Guangdong, China.,Chronic Disease Laboratory, Institutes for Life Sciences, South China University of Technology, Guangzhou, China
| | - Zhi-Bin Zhao
- Department of General Surgery, Guangzhou Digestive Disease Center, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, Guangdong, China.,Chronic Disease Laboratory, Institutes for Life Sciences, South China University of Technology, Guangzhou, China
| | - Fang Wei
- Department of General Surgery, Guangzhou Digestive Disease Center, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, Guangdong, China
| | - Yuan Yao
- Department of General Surgery, Guangzhou Digestive Disease Center, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, Guangdong, China
| | - Wen-Jing Qiu
- Department of General Surgery, Guangzhou Digestive Disease Center, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, Guangdong, China
| | - Zi-Xin Wu
- Department of General Surgery, Guangzhou Digestive Disease Center, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, Guangdong, China
| | - Qing-Qing Luo
- Department of General Surgery, Guangzhou Digestive Disease Center, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, Guangdong, China
| | - Wei Liu
- Department of General Surgery, Guangzhou Digestive Disease Center, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, China
| | - Yi-Bo Quan
- Department of General Surgery, Guangzhou Digestive Disease Center, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, Guangdong, China
| | - Zhe-Xiong Lian
- Department of General Surgery, Guangzhou Digestive Disease Center, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, Guangdong, China.,Chronic Disease Laboratory, Institutes for Life Sciences, South China University of Technology, Guangzhou, China
| | - Jie Cao
- Department of General Surgery, Guangzhou Digestive Disease Center, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, Guangdong, China
| |
Collapse
|
|
42
|
Zhu L, Xu Z, Wu Y, Liu P, Qian J, Yu S, Xia B, Lai J, Ma S, Wu Z. Prophylactic chemotherapeutic hyperthermic intraperitoneal perfusion reduces peritoneal metastasis in gastric cancer: a retrospective clinical study. BMC Cancer 2020; 20:827. [PMID: 32867714 PMCID: PMC7461269 DOI: 10.1186/s12885-020-07339-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2020] [Accepted: 08/25/2020] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Peritoneal metastasis is the most frequent failure in gastric cancer. This study evaluated the role of prophylactic chemotherapeutic hyperthermic intraperitoneal perfusion (CHIP) in patients after D2 dissection. METHODS Gastric cancer patients after D2 dissection were enrolled in this study. Patients received either chemotherapy (IV group) or CHIP (CHIP group). Sites of recurrence or metastasis, disease-free survival (DFS), overall survival (OS) and adverse events were evaluated. RESULTS Twenty-two patients received CHIP treatment, and 21 patients received chemotherapy alone. The median DFS time was 24.5 and 36.5 months in the IV group and CHIP group (P = 0.044), respectively. The median OS time was 33.1 months in the IV group and not reached in the CHIP group (P = 0.037). We also found that CHIP could reduce the total recurrence/metastasis rate, especially that of peritoneal metastasis. In the subgroup analysis, DFS and OS were both superior in deficient mismatch repair (dMMR) patients than in proficient MMR (pMMR) patients. CONCLUSION This hypothesis-generating study indicates that CHIP might be feasible for gastric cancer patients after D2 resection.
Collapse
Affiliation(s)
- Lucheng Zhu
- Department of Radiotherapy, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Hangzhou Cancer Hospital, Hangzhou, 310002, P.R. China
- Department of Oncology, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, P.R. China
| | - Zhizheng Xu
- Department of oncology, Changxing people's hospital, Huzhou, 313100, P.R. China
| | - Yajun Wu
- The Second Clinical Medical College of Zhejiang Chinese Medical University, Hangzhou, 310053, P.R. China
| | - Pengyuan Liu
- The Second Clinical Medical College of Zhejiang Chinese Medical University, Hangzhou, 310053, P.R. China
| | - Jianing Qian
- The Second Clinical Medical College of Zhejiang Chinese Medical University, Hangzhou, 310053, P.R. China
| | - Shuhuan Yu
- Department of Oncology, Zhejiang Hospital, Hangzhou, Zhejiang, 310013, P.R. China
| | - Bing Xia
- Department of Radiotherapy, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Hangzhou Cancer Hospital, Hangzhou, 310002, P.R. China
- Department of Oncology, Jiande Second People's Hospital, Zhejiang, 311604, P.R. China
| | - Jianjun Lai
- Department of Oncology, Zhejiang Hospital, Hangzhou, Zhejiang, 310013, P.R. China
| | - Shenglin Ma
- Department of Oncology, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, P.R. China.
| | - Zhibing Wu
- Department of Oncology, Zhejiang Hospital, Hangzhou, Zhejiang, 310013, P.R. China.
| |
Collapse
|
|
43
|
Wu Z, Liu J, Dai R, Wu S. Current status and future perspectives of immunotherapy in bladder cancer treatment. SCIENCE CHINA-LIFE SCIENCES 2020; 64:512-533. [PMID: 32926318 DOI: 10.1007/s11427-020-1768-y] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/21/2020] [Accepted: 06/23/2020] [Indexed: 12/12/2022]
Abstract
The treatment strategy of bladder cancer has evolved not only through the traditional modalities of surgery and chemotherapy but also by immunotherapy over the past several decades. Immunotherapies such as intravesical Bacillus Calmette-Guérin (BCG) vaccines and immune checkpoint blockades (ICBs) are sometimes used for treating patients with bladder cancer, especially those who develop resistance to conventional first-line treatments such as surgery and chemotherapy. Unfortunately, it is a limited number of individuals that see clinical benefits from this approach, and complicating matters more is that many of these patients suffer severe immune-related adverse events (irAEs). If current momentum continues to result in improved response rates and managed irAEs, immunotherapy could be poised to revolutionize the landscape of urothelial carcinoma therapeutics.
Collapse
Affiliation(s)
- Zhangsong Wu
- Department of Urological Surgery, The Third Affiliated Hospital of Shenzhen University, Shenzhen University, Shenzhen, 518000, China.,Shenzhen Following Precision Medical Institute, The Third Affiliated Hospital of Shenzhen University, Shenzhen University, Shenzhen, 518000, China
| | - Jinjian Liu
- Department of Urological Surgery, The Third Affiliated Hospital of Shenzhen University, Shenzhen University, Shenzhen, 518000, China.,Shenzhen Following Precision Medical Institute, The Third Affiliated Hospital of Shenzhen University, Shenzhen University, Shenzhen, 518000, China
| | - Ruixiang Dai
- Department of Urological Surgery, The Third Affiliated Hospital of Shenzhen University, Shenzhen University, Shenzhen, 518000, China.,Shenzhen Following Precision Medical Institute, The Third Affiliated Hospital of Shenzhen University, Shenzhen University, Shenzhen, 518000, China
| | - Song Wu
- Department of Urological Surgery, The Third Affiliated Hospital of Shenzhen University, Shenzhen University, Shenzhen, 518000, China. .,Shenzhen Following Precision Medical Institute, The Third Affiliated Hospital of Shenzhen University, Shenzhen University, Shenzhen, 518000, China. .,Department of Urological Surgery, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, 510120, China.
| |
Collapse
|
|
44
|
Rus Bakarurraini NAA, Ab Mutalib NS, Jamal R, Abu N. The Landscape of Tumor-Specific Antigens in Colorectal Cancer. Vaccines (Basel) 2020; 8:E371. [PMID: 32664247 PMCID: PMC7565947 DOI: 10.3390/vaccines8030371] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2020] [Revised: 06/22/2020] [Accepted: 06/22/2020] [Indexed: 12/24/2022] Open
Abstract
Over the last few decades, major efforts in cancer research and treatment have intensified. Apart from standard chemotherapy approaches, immunotherapy has gained substantial traction. Personalized immunotherapy has become an important tool for cancer therapy with the discovery of immune checkpoint inhibitors. Traditionally, tumor-associated antigens are used in immunotherapy-based treatments. Nevertheless, these antigens lack specificity and may have increased toxicity. With the advent of next-generation technologies, the identification of new tumor-specific antigens is becoming more important. In colorectal cancer, several tumor-specific antigens were identified and functionally validated. Multiple clinical trials from vaccine-based and adoptive cell therapy utilizing tumor-specific antigens have commenced. Herein, we will summarize the current landscape of tumor-specific antigens particularly in colorectal cancer.
Collapse
Affiliation(s)
| | | | - Rahman Jamal
- UKM Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia, Kuala Lumpur 56000, Malaysia; (N.A.A.R.B.); (N.S.A.M.)
| | - Nadiah Abu
- UKM Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia, Kuala Lumpur 56000, Malaysia; (N.A.A.R.B.); (N.S.A.M.)
| |
Collapse
|
|
45
|
Cervena K, Siskova A, Buchler T, Vodicka P, Vymetalkova V. Methylation-Based Therapies for Colorectal Cancer. Cells 2020; 9:E1540. [PMID: 32599894 PMCID: PMC7349319 DOI: 10.3390/cells9061540] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2020] [Revised: 06/22/2020] [Accepted: 06/23/2020] [Indexed: 02/08/2023] Open
Abstract
Colorectal carcinogenesis (CRC) is caused by the gradual long-term accumulation of both genetic and epigenetic changes. Recently, epigenetic alterations have been included in the classification of the CRC molecular subtype, and this points out their prognostic impact. As epigenetic modifications are reversible, they may represent relevant therapeutic targets. DNA methylation, catalyzed by DNA methyltransferases (DNMTs), regulates gene expression. For many years, the deregulation of DNA methylation has been considered to play a substantial part in CRC etiology and evolution. Despite considerable advances in CRC treatment, patient therapy response persists as limited, and their profit from systemic therapies are often hampered by the introduction of chemoresistance. In addition, inter-individual changes in therapy response in CRC patients can arise from their specific (epi)genetic compositions. In this review article, we summarize the options of CRC treatment based on DNA methylation status for their predictive value. This review also includes the therapy outcomes based on the patient's methylation status in CRC patients. In addition, the current challenge of research is to develop therapeutic inhibitors of DNMT. Based on the essential role of DNA methylation in CRC development, the application of DNMT inhibitors was recently proposed for the treatment of CRC patients, especially in patients with DNA hypermethylation.
Collapse
Affiliation(s)
- Klara Cervena
- Department of Molecular Biology of Cancer, Institute of Experimental Medicine, Videnska 1083, 14 200 Prague, Czech Republic; (K.C.); (A.S.); (P.V.)
- Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Albertov 4, 128 00 Prague, Czech Republic
| | - Anna Siskova
- Department of Molecular Biology of Cancer, Institute of Experimental Medicine, Videnska 1083, 14 200 Prague, Czech Republic; (K.C.); (A.S.); (P.V.)
- Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Albertov 4, 128 00 Prague, Czech Republic
| | - Tomas Buchler
- Department of Oncology, First Faculty of Medicine, Charles University and Thomayer Hospital, Videnska 800, 140 59 Prague, Czech Republic;
| | - Pavel Vodicka
- Department of Molecular Biology of Cancer, Institute of Experimental Medicine, Videnska 1083, 14 200 Prague, Czech Republic; (K.C.); (A.S.); (P.V.)
- Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Albertov 4, 128 00 Prague, Czech Republic
- Biomedical Centre, Faculty of Medicine in Pilsen, Charles University, Alej Svobody 76, 323 00 Pilsen, Czech Republic
| | - Veronika Vymetalkova
- Department of Molecular Biology of Cancer, Institute of Experimental Medicine, Videnska 1083, 14 200 Prague, Czech Republic; (K.C.); (A.S.); (P.V.)
- Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Albertov 4, 128 00 Prague, Czech Republic
- Biomedical Centre, Faculty of Medicine in Pilsen, Charles University, Alej Svobody 76, 323 00 Pilsen, Czech Republic
| |
Collapse
|
|
46
|
Kloor M, Reuschenbach M, Pauligk C, Karbach J, Rafiyan MR, Al-Batran SE, Tariverdian M, Jäger E, von Knebel Doeberitz M. A Frameshift Peptide Neoantigen-Based Vaccine for Mismatch Repair-Deficient Cancers: A Phase I/IIa Clinical Trial. Clin Cancer Res 2020; 26:4503-4510. [PMID: 32540851 DOI: 10.1158/1078-0432.ccr-19-3517] [Citation(s) in RCA: 95] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2019] [Revised: 04/02/2020] [Accepted: 06/10/2020] [Indexed: 11/16/2022]
Abstract
PURPOSE DNA mismatch repair (MMR) deficiency is a hallmark of Lynch syndrome, the most common inherited cancer syndrome. MMR-deficient cancer cells accumulate numerous insertion/deletion mutations at microsatellites. Mutations of coding microsatellites (cMS) lead to the generation of immunogenic frameshift peptide (FSP) neoantigens. As the evolution of MMR-deficient cancers is triggered by mutations inactivating defined cMS-containing tumor suppressor genes, distinct FSP neoantigens are shared by most MMR-deficient cancers. To evaluate safety and immunogenicity of an FSP-based vaccine, we performed a clinical phase I/IIa trial (Micoryx). PATIENTS AND METHODS The trial comprised three cycles of four subcutaneous vaccinations (FSP neoantigens derived from mutant AIM2, HT001, TAF1B genes) mixed with Montanide ISA-51 VG over 6 months. Inclusion criteria were history of MMR-deficient colorectal cancer (UICC stage III or IV) and completion of chemotherapy. Phase I evaluated safety and toxicity as primary endpoint (six patients), phase IIa addressed cellular and humoral immune responses (16 patients). RESULTS Vaccine-induced humoral and cellular immune responses were observed in all patients vaccinated per protocol. Three patients developed grade 2 local injection site reactions. No vaccination-induced severe adverse events occurred. One heavily pretreated patient with bulky metastases showed stable disease and stable CEA levels over 7 months. CONCLUSIONS FSP neoantigen vaccination is systemically well tolerated and consistently induces humoral and cellular immune responses, thus representing a promising novel approach for treatment and even prevention of MMR-deficient cancer.
Collapse
Affiliation(s)
- Matthias Kloor
- Department of Applied Tumor Biology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany. .,Clinical Cooperation Unit Applied Tumor Biology, DKFZ (German Cancer Research Center) Heidelberg, Heidelberg, Germany.,Molecular Medicine Partnership Unit (MMPU), EMBL Heidelberg, Heidelberg, Germany
| | - Miriam Reuschenbach
- Department of Applied Tumor Biology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.,Clinical Cooperation Unit Applied Tumor Biology, DKFZ (German Cancer Research Center) Heidelberg, Heidelberg, Germany.,Molecular Medicine Partnership Unit (MMPU), EMBL Heidelberg, Heidelberg, Germany
| | - Claudia Pauligk
- Institute of Clinical Cancer Research (IKF), Krankenhaus Nordwest, UCT University Cancer Center, Frankfurt, Germany
| | - Julia Karbach
- Clinic for Oncology and Hematology, Krankenhaus Nordwest, Frankfurt, Germany
| | | | - Salah-Eddin Al-Batran
- Institute of Clinical Cancer Research (IKF), Krankenhaus Nordwest, UCT University Cancer Center, Frankfurt, Germany
| | - Mirjam Tariverdian
- Department of Surgery, University Hospital Heidelberg, Heidelberg, Germany
| | - Elke Jäger
- Clinic for Oncology and Hematology, Krankenhaus Nordwest, Frankfurt, Germany
| | - Magnus von Knebel Doeberitz
- Department of Applied Tumor Biology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.,Clinical Cooperation Unit Applied Tumor Biology, DKFZ (German Cancer Research Center) Heidelberg, Heidelberg, Germany.,Molecular Medicine Partnership Unit (MMPU), EMBL Heidelberg, Heidelberg, Germany
| |
Collapse
|
|
47
|
Yu H, Han L, Yuan J, Sun Y. Circulating tumor cell free DNA from plasma and urine in the clinical management of colorectal cancer. Cancer Biomark 2020; 27:29-37. [PMID: 31658042 DOI: 10.3233/cbm-182344] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
BACKGROUND Tissue biopsy remains the conventional technique for tumor genotyping. The main limitations are it is invasive and provides only partial snapshot during disease progression. Liquid biopsy approaches via plasma and urine are possible alternatives, and the current study aims to provide comparative analyses for plasma and urine derived disease genotyping. METHODS Blood and urine specimens were collected from 150 individuals with metastatic colorectal cancer (mCRC). Patients had multiple metastases and advanced stages of cancer. Common genetic mutations including KRAS and BRAF genetic abnormalities were evaluated. Patients were also serially monitored and compared. RESULTS In all cases, plasma and urine cell free DNA were successfully recovered and were of good quality for genetic analysis. Median recovered DNA from both urine and plasma samples were higher in mCRC patients than healthy volunteers indicating disease associations. Among the identified mutations, matched tumor tissue profiles compared to results from plasma ctDNA was 92%. For urine cell free DNA, the concordance among the identified mutations was 91%. Both sample types were closely matched to reference standards of tissue biopsy and indicated good clinical utility. Serial measurements indicated trends within each patient group that was linked with disease outcome. CONCLUSIONS In the current study, our data indicated that both plasma and urine cell free DNA can be utilized to address possible disease progression in colorectal cancer patients. More importantly, this also provide risk stratifications that correlated to disease outcome. This can potentially aid in early clinical intervention for patients with possibly worse outcomes.
Collapse
|
|
48
|
Cerretelli G, Ager A, Arends MJ, Frayling IM. Molecular pathology of Lynch syndrome. J Pathol 2020; 250:518-531. [PMID: 32141610 DOI: 10.1002/path.5422] [Citation(s) in RCA: 101] [Impact Index Per Article: 20.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2020] [Revised: 03/02/2020] [Accepted: 03/03/2020] [Indexed: 12/18/2022]
Abstract
Lynch syndrome (LS) is characterised by predisposition to colorectal, endometrial, and other cancers and is caused by inherited pathogenic variants affecting the DNA mismatch repair (MMR) genes MLH1, MSH2, MSH6, and PMS2. It is probably the most common predisposition to cancer, having an estimated prevalence of between 1/100 and 1/180. Resources such as the International Society for Gastrointestinal Hereditary Cancer's MMR gene variant database, the Prospective Lynch Syndrome Database (PLSD), and the Colon Cancer Family Register (CCFR), as well as pathological and immunological studies, are enabling advances in the understanding of LS. These include defined criteria by which to interpret gene variants, the function of MMR in the normal control of apoptosis, definition of the risks of the various cancers, and the mechanisms and pathways by which the colorectal and endometrial tumours develop, including the critical role of the immune system. Colorectal cancers in LS can develop along three pathways, including flat intramucosal lesions, which depend on the underlying affected MMR gene. This gives insights into the limitations of colonoscopic surveillance and highlights the need for other forms of anti-cancer prophylaxis in LS. Finally, it shows that the processes of autoimmunisation and immunoediting fundamentally constrain the development of tumours in LS and explain the efficacy of immune checkpoint blockade therapy in MMR-deficient tumours. © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Collapse
Affiliation(s)
- Guia Cerretelli
- Division of Pathology, Cancer Research UK Edinburgh Centre, University of Edinburgh, Edinburgh, UK
| | - Ann Ager
- Division of Infection and Immunity, School of Medicine and Systems Immunity Research Institute, Cardiff University, Cardiff, UK
| | - Mark J Arends
- Division of Pathology, Cancer Research UK Edinburgh Centre, University of Edinburgh, Edinburgh, UK
| | - Ian M Frayling
- Inherited Tumour Syndromes Research Group, Institute of Cancer & Genetics, School of Medicine, Cardiff University, Cardiff, UK
| |
Collapse
|
|
49
|
Reustle A, Di Marco M, Meyerhoff C, Nelde A, Walz JS, Winter S, Kandabarau S, Büttner F, Haag M, Backert L, Kowalewski DJ, Rausch S, Hennenlotter J, Stühler V, Scharpf M, Fend F, Stenzl A, Rammensee HG, Bedke J, Stevanović S, Schwab M, Schaeffeler E. Integrative -omics and HLA-ligandomics analysis to identify novel drug targets for ccRCC immunotherapy. Genome Med 2020; 12:32. [PMID: 32228647 PMCID: PMC7106651 DOI: 10.1186/s13073-020-00731-8] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2019] [Accepted: 03/12/2020] [Indexed: 12/24/2022] Open
Abstract
Background Clear cell renal cell carcinoma (ccRCC) is the dominant subtype of renal cancer. With currently available therapies, cure of advanced and metastatic ccRCC is achieved only in rare cases. Here, we developed a workflow integrating different -omics technologies to identify ccRCC-specific HLA-presented peptides as potential drug targets for ccRCC immunotherapy. Methods We analyzed HLA-presented peptides by MS-based ligandomics of 55 ccRCC tumors (cohort 1), paired non-tumor renal tissues, and 158 benign tissues from other organs. Pathways enriched in ccRCC compared to its cell type of origin were identified by transcriptome and gene set enrichment analyses in 51 tumor tissues of the same cohort. To retrieve a list of candidate targets with involvement in ccRCC pathogenesis, ccRCC-specific pathway genes were intersected with the source genes of tumor-exclusive peptides. The candidates were validated in an independent cohort from The Cancer Genome Atlas (TCGA KIRC, n = 452). DNA methylation (TCGA KIRC, n = 273), somatic mutations (TCGA KIRC, n = 392), and gene ontology (GO) and correlations with tumor metabolites (cohort 1, n = 30) and immune-oncological markers (cohort 1, n = 37) were analyzed to characterize regulatory and functional involvements. CD8+ T cell priming assays were used to identify immunogenic peptides. The candidate gene EGLN3 was functionally investigated in cell culture. Results A total of 34,226 HLA class I- and 19,325 class II-presented peptides were identified in ccRCC tissue, of which 443 class I and 203 class II peptides were ccRCC-specific and presented in ≥ 3 tumors. One hundred eighty-five of the 499 corresponding source genes were involved in pathways activated by ccRCC tumors. After validation in the independent cohort from TCGA, 113 final candidate genes remained. Candidates were involved in extracellular matrix organization, hypoxic signaling, immune processes, and others. Nine of the 12 peptides assessed by immunogenicity analysis were able to activate naïve CD8+ T cells, including peptides derived from EGLN3. Functional analysis of EGLN3 revealed possible tumor-promoting functions. Conclusions Integration of HLA ligandomics, transcriptomics, genetic, and epigenetic data leads to the identification of novel functionally relevant therapeutic targets for ccRCC immunotherapy. Validation of the identified targets is recommended to expand the treatment landscape of ccRCC.
Collapse
Affiliation(s)
- Anna Reustle
- Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany.,University of Tuebingen, Tuebingen, Germany
| | - Moreno Di Marco
- Department of Immunology, Institute for Cell Biology, University of Tuebingen, Tuebingen, Germany
| | - Carolin Meyerhoff
- Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany.,University of Tuebingen, Tuebingen, Germany
| | - Annika Nelde
- Department of Immunology, Institute for Cell Biology, University of Tuebingen, Tuebingen, Germany.,Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), University Hospital Tuebingen, Tuebingen, Germany.,German Cancer Consortium (DKTK), Partner Site Tuebingen, Tuebingen, Germany
| | - Juliane S Walz
- Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), University Hospital Tuebingen, Tuebingen, Germany.,German Cancer Consortium (DKTK), Partner Site Tuebingen, Tuebingen, Germany.,iFIT Cluster of Excellence (EXC 2180) "Image-Guided and Functionally Instructed Tumor Therapies", University of Tuebingen, Tuebingen, Germany
| | - Stefan Winter
- Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany.,University of Tuebingen, Tuebingen, Germany
| | - Siahei Kandabarau
- Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany.,University of Tuebingen, Tuebingen, Germany
| | - Florian Büttner
- Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany.,University of Tuebingen, Tuebingen, Germany
| | - Mathias Haag
- Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany.,University of Tuebingen, Tuebingen, Germany
| | - Linus Backert
- Department of Immunology, Institute for Cell Biology, University of Tuebingen, Tuebingen, Germany
| | - Daniel J Kowalewski
- Department of Immunology, Institute for Cell Biology, University of Tuebingen, Tuebingen, Germany
| | - Steffen Rausch
- Department of Urology, University Hospital Tuebingen, Tuebingen, Germany
| | - Jörg Hennenlotter
- Department of Urology, University Hospital Tuebingen, Tuebingen, Germany
| | - Viktoria Stühler
- Department of Urology, University Hospital Tuebingen, Tuebingen, Germany
| | - Marcus Scharpf
- Institute of Pathology and Neuropathology, University Hospital Tuebingen, Tuebingen, Germany
| | - Falko Fend
- Institute of Pathology and Neuropathology, University Hospital Tuebingen, Tuebingen, Germany
| | - Arnulf Stenzl
- Department of Urology, University Hospital Tuebingen, Tuebingen, Germany
| | - Hans-Georg Rammensee
- Department of Immunology, Institute for Cell Biology, University of Tuebingen, Tuebingen, Germany.,German Cancer Consortium (DKTK), Partner Site Tuebingen, Tuebingen, Germany.,iFIT Cluster of Excellence (EXC 2180) "Image-Guided and Functionally Instructed Tumor Therapies", University of Tuebingen, Tuebingen, Germany
| | - Jens Bedke
- Department of Urology, University Hospital Tuebingen, Tuebingen, Germany
| | - Stefan Stevanović
- Department of Immunology, Institute for Cell Biology, University of Tuebingen, Tuebingen, Germany.,German Cancer Consortium (DKTK), Partner Site Tuebingen, Tuebingen, Germany.,iFIT Cluster of Excellence (EXC 2180) "Image-Guided and Functionally Instructed Tumor Therapies", University of Tuebingen, Tuebingen, Germany
| | - Matthias Schwab
- Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany. .,University of Tuebingen, Tuebingen, Germany. .,German Cancer Consortium (DKTK), Partner Site Tuebingen, Tuebingen, Germany. .,iFIT Cluster of Excellence (EXC 2180) "Image-Guided and Functionally Instructed Tumor Therapies", University of Tuebingen, Tuebingen, Germany. .,Departments of Clinical Pharmacology, Pharmacy and Biochemistry, University of Tuebingen, Tuebingen, Germany.
| | - Elke Schaeffeler
- Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany.,University of Tuebingen, Tuebingen, Germany.,iFIT Cluster of Excellence (EXC 2180) "Image-Guided and Functionally Instructed Tumor Therapies", University of Tuebingen, Tuebingen, Germany
| |
Collapse
|
|
50
|
Abstract
The development of cancer results from the evolutionary balance between the proliferating aptitude of cancer cells and the response of the host's tissues. Some cancers are characterized by genetic instability dependent upon impaired DNA repair mechanisms that lead to the chaotic disruption of multiple cellular functions often in excess of the cancer survival needs and may exert broad effects on surrounding tissues, some beneficial and some detrimental to cancer growth. Among them, inflammatory processes that accompany wound healing may initiate a reaction of the host against the neo-formation. This is possibly triggered by the release by dying cancer cells of molecules known as Damage-Associated Molecular Patterns (DAMPs) following a process termed Immunogenic Cell Death (ICD) that initiates an immune response through innate and adaptive mechanisms. Indeed, analysis of large cancer data sets has shown that ICD is strictly associated with the activation of other immune effector or immune-regulatory pathways. Here, we will describe how immune activation and compensatory immune-regulatory mechanisms balance anti-cancer immune surveillance and the roles that innate and adaptive immunity play including the weight that neo-epitopes may exert as initiators and sculptors of high-affinity memory and effector immune responses against cancer. We will discuss the evolutionary basis for the existence of immune checkpoints and how several theories raised to explain cancer resistance to immunotherapy represent a facet of a similar evolutionary phenomenon that we described in the Theory of Everything. We will show how the biology of immunogenicity and counterbalancing immune regulation is widespread across cancers independent of their ontogenesis while subtle idiosyncratic differences are discernible among them. Finally, we will suggest that overcoming immune resistance implies distinct approaches relevant to the immune context of individual cancers.
Collapse
|