The landscape of antigen-specific T cells in human cancers

Antigen-specific T cells can be orchestrated to kill cancer cells in immunotherapies but the utilities of the TCR information have not been fully explored. Here, we leveraged previous efforts on tumor TCR repertoire, and developed a novel algorithm to characterize antigen-specific TCR clusters. Joint analysis with gene expression revealed novel regulators for T cell activation. Investigation of single-cell sequencing data revealed a novel subset of tissue-resident memory T cell population with elevated metabolic status. Integrative analysis of TCR clusters with HLA alleles and cancer genomics data identified candidate antigens derived from missense mutations, frameshift indels, and tumor-associated gene overexpression. Predicted antigen HSFX1 was further validated using vaccinated humanized HLA-A*02:01 mice. Finally, high abundant cancer-associated TCRs were observed in the blood repertoire of early breast cancer patients, suggesting new avenues for non- invasive early detection. Thus, our analysis identified cancer-associated T cells with broad utilities in immune monitoring and cancer immunotherapies.