Publication
Autoreactive napsin A-specific T cells are enriched in lung tumors and inflammatory lung lesions during immune checkpoint blockade.
Journal Paper/Review - Sep 2, 2022
Berner Fiamma, Bomze David, Lichtensteiger Christa, Walter Vincent, Niederer Rebekka, Hasan Ali Omar, Wyss Nina, Bauer Jens, Freudenmann Lena Katharina, Marcu Ana, Wolfschmitt Eva-Maria, Haen Sebastian, Gross Thorben, Abdou Marie-Therese, Diem Stefan, Knöpfli Stella, Sinnberg Tobias, Hofmeister Kathrin, Cheng Hung-Wei, Toma Marieta, Klümper Niklas, Purde Mette-Triin, Pop Oltin Tiberiu, Jochum Ann-Kristin, Pascolo Steve, Jörger Markus, Früh Martin, Jochum Wolfram, Rammensee Hans-Georg, Läubli Heinz, Hölzel Michael, Neefjes Jacques, Walz Juliane, Flatz Lukas
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Brief description/objective
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.