Cancer-specific T cell receptor discovery using 150,000 clinical genomics samples

T cell receptors (TCRs) can enable detection and elimination of cancer cells via recognition of cancer-specific peptides presented on human leukocyte antigen (HLA). We speculated that shared cancer antigens could be recognized by recurrent (“public”) TCRs, which might be identifiable using statistical methods. Here, we identified public TCRs against therapeutically relevant targets via computational analysis of large-scale bulk RNA sequencing data obtained from routine clinical genomics testing. Using data from ∼150,000 patient tumor samples, we identified TCR chains that were associated with well-known cancer antigens, including human papillomavirus, mutated KRAS, and CT83. We devised methods for pairing enriched TCR-α and TCR-β chain sequences and validated 44 TCRs across nine peptide-HLA targets for antigen recognition, including potent cytotoxic TCRs. Our results suggest that public anticancer TCRs are common and may represent a new source for the development of cancer therapeutics.