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Autoreactive napsin A–specific T cells are enriched in lung tumors and inflammatory lung lesions during immune checkpoint blockade

Cancer treatment with immune checkpoint blockade (ICB) often induces immune-related adverse events (irAEs). We hypothesized that proteins coexpressed in tumors and normal cells could be antigenic targets in irAEs and herein described DITAS (discovery of tumor-associated self-antigens) for their identification. DITAS computed transcriptional similarity between lung tumors and healthy lung tissue based on single-sample gene set enrichment analysis. This identified 10 lung tissue–specific genes highly expressed in the lung tumors. Computational analysis was combined with functional T cell assays and single-cell RNA sequencing of the antigen-specific T cells to validate the lung tumor self-antigens. In patients with non–small cell lung cancer (NSCLC) treated with ICB, napsin A was a self-antigen that elicited strong CD8+ T cell responses, with ICB responders harboring higher frequencies of these CD8+ T cells compared with nonresponders. Human leukocyte antigen (HLA) class I ligands derived from napsin A were present in human lung tumors and in nontumor lung tissues, and napsin A tetramers confirmed the presence of napsin A–specific CD8+ T cells in blood and tumors of patients with NSCLC. Napsin A–specific T cell clonotypes were enriched in lung tumors and ICB-induced inflammatory lung lesions and could kill immortalized HLA-matched NSCLC cells ex vivo. Single-cell RNA sequencing revealed that these T cell clonotypes expressed proinflammatory cytokines and cytotoxic markers. Thus, DITAS successfully identified self-antigens, including napsin A, that likely mediate effective antitumor T cell responses in NSCLC and may simultaneously underpin lung irAEs. Description We share a method called DITAS for the identification of tumor antigens in immune checkpoint blockade-treated cancer patients. irAE causing T cells in lung cancer Despite the success of immune checkpoint blockade (ICB) in cancer, the efficacy is limited by immune-related adverse events (irAEs) that require treatment cessation. Thus, identifying peptides that induce both antitumor and irAE responses is crucial to improving ICB. Here, Berner et al. developed a method, DITAS (discovery of tumor-associated self-antigens) for detecting these peptides. DITAS involved analyzing the shared antigens between non–small cell lung cancer (NSCLC) and lung tissue, then performing immunopeptidomes, determining which HLA these peptides bound to, predicting the CD8+ T cell epitopes of these peptides, performing functional validation, and lastly identifying their candidate antigens. Using this method, the authors identified napsin A, which induced NSCLC and lung reactive T cells. Thus, DITAS could be used to identify irAE causing T cells.