LAUSR

The accurate identification of antitumor T cell receptors (TCRs) represents a major challenge for the engineering of cell-based cancer immunotherapies. By mapping 55 neoantigen-specific TCR clonotypes (NeoTCRs) from 10 metastatic human tumors to their single-cell transcriptomes, we identified signatures of CD8+ and CD4+ neoantigen-reactive tumor-infiltrating lymphocytes (TILs). Neoantigen-specific TILs exhibited tumor-specific expansion with dysfunctional phenotypes, distinct from blood-emigrant bystanders and regulatory TILs. Prospective prediction and testing of 73 NeoTCR signature–derived clonotypes demonstrated that half of the tested TCRs recognized tumor antigens or autologous tumors. NeoTCR signatures identified TCRs that target driver neoantigens and nonmutated viral or tumor-associated antigens, suggesting a common metastatic TIL exhaustion program. NeoTCR signatures delineate the landscape of TILs across metastatic tumors, enabling successful TCR prediction based purely on TIL transcriptomic states for use in cancer immunotherapy. Description Shared states of tumor-specific T cells Adoptive cell therapy is a type of cancer immunotherapy in which an individual’s immune system is trained to eliminate their tumor. This process involves genetically engineering T cells, but it requires the challenging identification of T cell receptors (TCRs) that can recognize cancer-specific alterations. Lowery and Krishna examined TCRs from human metastatic tumors, including those of breast, melanoma, and colon origin. Using TCR and single-cell sequencing technology, the authors found a conserved phenotypic state common to known tumor mutation-specific T cells. Gene signatures were able to predict the tumor reactivity of TCRs from independent samples and discriminate them from bystander T cells. Such strategies may enable more streamlined identification of tumor-specific TCRs for patient immunotherapy. —PNK The transcriptomic landscape of tumor mutation–reactive T cells is elucidated for cancer immunotherapy