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

Science immunology

Authors: Fiamma Berner, David Bomze, Christa Lichtensteiger, Vincent Walter, Rebekka Niederer, Omar Hasan Ali, Nina Wyss, Jens Bauer, Lena Katharina Freudenmann, Ana Marcu, Eva-Maria Wolfschmitt, Sebastian Haen, Thorben Gross, Marie-Therese Abdou, Stefan Diem, Stella Knöpfli, Tobias Sinnberg, Kathrin Hofmeister, Hung-Wei Cheng, Marieta Toma, Niklas Klümper, Mette-Triin Purde, Oltin Tiberiu Pop, Ann-Kristin Jochum, Steve Pascolo, Markus Joerger, Martin Früh, Wolfram Jochum, Hans-Georg Rammensee, Heinz Läubli, Michael Hölzel, Jacques Neefjes, Juliane Walz, Lukas Flatz

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.

PMID: 36054337

Participating cluster members