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

Abstract

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.

Recent advances in cancer immunotherapy

“…While there are a number of distinct HLA, each one displaying different peptides with different affinity, current cancer immunotherapy can only target a limited set of HLA isoforms, severely restricting its accessibility to patients. More recently, Hirano and Mak have developed a new strategy that they validated in 8 patients with melanoma [ 103 ]. Generating a library of peptide exchangable HLA-peptide multimers to activate Tumour Infiltrating Lymphocytes (TIL).…”

“…With 25 forms of HLA to display over 800 peptides, the authors were able to select A*02:01/MART1 27-35 as a relevant immunological hotspot, with the successful staining up to 9.2% of the polyclonally expanded TILs. Using this rationale [ 104 ], they further identified shared antigenic epitopes recognized by melanoma TILs and their cloned TCRs, for the development of novel cancer immunotherapy [ 103 ]. This, certainly changes the landscape of tumour immunotherapy [ 105 ].…”

Fundamental and Essential Knowledge for Pathologists Engaged in the Research and Practice of Immune Checkpoint Inhibitor-Based Cancer Immunotherapy

“…A recently published study revealed that malignant melanoma tissue harbors numerous tumor-infiltrating lymphocytes, which are self-antigen cognitive (45). Significantly, antigen spreading, a cardinal process for effective cancer immunotherapy, can potentiate not only neo-antigens but also self-antigens during the killing of tumor cells (46)(47)(48).…”

T cells discriminate between groups C1 and C2 HLA-C

“…In psoriasis, the strongest genetic association is with HLA-C*06:02, thought to be mediated by HLA-C*06:02 restricted T cells (Chen and Tsai, 2018;Lande et al, 2014). Furthermore, recent efforts to define the specificities of tumor infiltrating lymphocytes (TIL), readily identified HLA-C restricted T cells (Levin et al, 2021;Lu et al, 2014;Murata et al, 2020;Tran et al, 2015;Tran et al, 2016). Most notably, multiple HLA-C*08:02 restricted TCRs specific for the oncogenic hotspot mutation KRAS-G12D were identified in multiple cancer patients (Tran et al, 2015;Tran et al, 2016).…”