Landscape mapping of shared antigenic epitopes and their cognate TCRs of tumor-infiltrating T lymphocytes in melanoma.

HLA-restricted T cell responses can induce antitumor effects in cancer patients. Previous human T cell research has largely focused on the few HLA alleles prevalent in a subset of ethnic groups. Here, using a panel of newly developed peptide-exchangeable peptide/HLA multimers and artificial antigen-presenting cells for 25 different class I alleles and greater than 800 peptides, we systematically and comprehensively mapped shared antigenic epitopes recognized by tumor-infiltrating T lymphocytes (TILs) from eight melanoma patients for all their class I alleles. We were able to determine the specificity, on average, of 12.2% of the TILs recognizing a mean of 3.1 shared antigen-derived epitopes across HLA-A, B, and C. Furthermore, we isolated a number of cognate T cell receptor genes with tumor reactivity. Our novel strategy allows for a more complete examination of the immune response and development of novel cancer immunotherapy not limited by HLA allele prevalence or tumor mutation burden. The immune system is the body’s way of defending itself, offering protection against diseases such as cancer. But to remove the cancer cells, the immune system must be able to identify them as different from the rest of the body. All cells break down proteins into shorter fragments, known as peptides, that are displayed on the cell surface by a protein called human leukocyte antigen, HLA for short. Cancer cells display distinctive peptides on their surface as they generate different proteins to those of healthy cells. Immune cells called T cells use these abnormal peptides to identify the cancer so that it can be destroyed. Sometimes T cells can lack the right equipment to detect abnormal peptides, allowing cancer cells to hide from the immune system. However, T cells can be trained through a treatment called immunotherapy, which provides T cells with new tools so that they can spot the peptides displayed by HLA on the previously ‘hidden’ cancer cells. There are many different forms of HLA, each of which can display different peptides. Current research in immunotherapy commonly targets only a subset of HLA forms, and not all cancer patients have these types. This means that immunotherapy research is only likely to be of most benefit to a limited number of patients. Immunotherapy could be made effective for more people if new cancer peptides that are displayed by the other ‘under-represented’ forms of HLA were identified. Murata, Nakatsugawa et al. have now used T cells that were taken from tumors in eight patients with melanoma, which is a type of skin cancer. A library of fluorescent HLA-peptides was generated – using a new, simplified methodology – with 25 forms of HLA that displayed over 800 peptides. T cells were then mixed with the library to identify which HLA-peptides they can target. As a result, Murata, Nakatsugawa et al. found the cancer targets of around 12% of the tumor-infiltrating T cells tested, including those from under-represented forms of HLA. Consequently, these findings could be used to develop new immunotherapies that can treat more patients.

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© 2020, Murata et al.

Déclaration de conflit d'intérêts

KM The University Health Network has filed patent application related to this study on which Kenji Murata is named as an inventor (US16/095,913, US62/813,639, US62/813,642, US62/813,644, US62/813,645, US62/813,647, US62/813,650, US62/813,651, and US62/823,487). MN The University Health Network has filed patent application related to this study on which Munehide Nakatsugawa is named as an inventor (US16/095,913). MR The University Health Network has filed patent application related to this study on which Muhammed A. Rahman is named as an inventor (US16/095,913). LN, DM, DM, KS, HS, YM, YK, TG, MA, CW, BB, DL, AE, DG, MR, DG, TP, TM, PO No competing interests declared, KS The University Health Network has filed patent application related to this study on which Kayoko Saso is named as an inventor (US62/813,639, US62/813,642, US62/813,644, US62/813,645, US62/813,647, US62/813,650, US62/813,651, and US62/823,487). MB Marcus O. Butler has served on advisory boards for Merck, BMS, Novartis, GSK, Immunocore, immunovaccine, Sanofi, and EMD Serono and received research funding for investigator initiated clinical trials from Merck and Takara Bio. NH Naoto Hirano reports receiving a research grant from and is a consultant for Takara Bio and Otsuka Pharmaceutical and serving on an advisory board for F. Hoffmann-La Roche. The University Health Network has filed patent application related to this study on which Naoto Hirano is named as an inventor (US16/095,913, US62/813,639, US62/813,642, US62/813,644, US62/813,645, US62/813,647, US62/813,650, US62/813,651, and US62/823,487).