Antigen specificity of tumor-infiltrating lymphocytes (TILs) in non-small cell lung cancer (NSCLC)
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Abstract
Increasing the total numbers of tumor-specific lymphocytes among T cell populations used for adoptive cell therapies could dramatically increase overall tumor eradication efficiencies in cancer patients. By analyzing T cell receptor (TCR) repertoires in tumor and adjacent normal tissues of three non-small cell lung cancer patients, this study used an antigen-agnostic approach to identify potentially tumor-specific TCR clonotypes in highly heterogenous tumor-infiltrating lymphocyte (TIL) populations. Hence, TCRs from tumor-enriched and programmed cell death protein 1 (PD-1)-positive TILs were used to generate transgenic TCR-T cells via retroviral transduction of healthy donor lymphocytes. When tested for the recognition of patient-specific neoantigen candidates, three patient P18-derived TCRs specifically recognized a mutated KRASQ61H neoantigen via HLA-A*01:01. Moreover, the three KRASQ61H-specific TCRs formed a specificity cluster exhibiting highly homologous CDR3 antigen recognition motifs. Hence, TCRs from two additional specificity clusters were analyzed that mediated similar reactivity patterns when tested on partially HLA-matched allogeneic cell lines. Consistent with the literature, TCRs of cluster G recognized two pathogen-derived antigens and the non-mutated tumor-associated antigen TMEM161A via HLA-A*02:01. In summary, nine tumor-reactive TCRs were identified either recognizing the KRASQ61H neoantigen or TMEM161A. Therefore, the presented data substantially support the efforts to further develop antigen-agnostic, personalized T cell immunotherapies.