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

Berner, F.; Bomze, D.; Lichtensteiger, C.; Walter, V.; Niederer, R.; Ali, O.H.; Wyss, N.; Bauer, J.; Freudenmann, L.K.; Marcu, A.; Wolfschmitt, E.M.; Haen, S.; Gross, T.; Abdou, M.T.; Diem, S.; Knopfli, S.; Sinnberg, T.; Hofmeister, K.; Cheng, H.W.; Toma, M.; Klumper, N.; Purde, M.T.; Pop, O.T.; Jochum, A.K.; Pascolo, S.; Joerger, M.; Fruh, M.; Jochum, W.; Rammensee, H.G.; Laubli, H.; Holzel, M.; Neefjes, J.; Walz, J.; Flatz, L.

doi:doi:10.1126/sciimmunol.abn9644

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...Show moreCancer 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 Awere 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.Show less

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