Autoreactive napsin A–specific T cells are enriched in lung tumors and inflammatory lung lesions during immune checkpoint blockade
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 P. 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 T. Pop, Ann-Kristin Jochum, Steve Pascolo, Markus Joerger, Martin Früh, Wolfram Jochum, Hans‐Georg Rammensee, Heinz Läubli, Michael Hölzel, Jacques Neefjes, Juliane S. Walz, Lukas Flatz
Abstract
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.