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.
Highlights
Cancer immunotherapy is a cancer treatment that is designed to harness the power of the body’s immune system to fight cancer (Finn, 2018a)
To functionally detect HLArestricted antigen-specific T cell responses, we previously demonstrated the versatility of gene-engineered artificial antigen-presenting cells (APCs) individually expressing various class I alleles as a single HLA allele (Butler and Hirano, 2014)
It is well established that melanoma TILs contain antitumor T cells that are specific for both non-mutated and mutated antigens (Andersen et al, 2012; Bentzen et al, 2016; Duhen et al, 2018; Ye et al, 2014)
Summary
Cancer immunotherapy is a cancer treatment that is designed to harness the power of the body’s immune system to fight cancer (Finn, 2018a). 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 These findings could be used to develop new immunotherapies that can treat more patients. Unlike comparable methods (Andersen et al, 2012; Migueles et al, 2000), our novel pHLA multimer technology enables a one-step peptide exchange in one tube and is more effective in class I alleles that are difficult to produce in bacteria. These technical advantages allow for a rapid, versatile, and less labor-intensive examination of the immune response. Our strategy using a paired library of the novel pHLA multimer and human cell-based artificial APC system enables identification of novel class I epitopes and detection of cognate T cells in a comprehensive and systematic way
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