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

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; ... (2022). Autoreactive napsin A-specific T cells are enriched in lung tumors and inflammatory lung lesions during immune checkpoint blockade. Science immunology, 7(75), eabn9644. American Association for the Advancement of Science 10.1126/sciimmunol.abn9644

Text sciimmunol.abn9644.pdf - Published Version Restricted to registered users only Available under License Publisher holds Copyright. Download (1MB)

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.

Interest & Impact

Downloads

0 since deposited on 05 Sep 2022
0 in the past 12 months

Citations

5 Citations in Web of Science ®
6 Citations in Scopus

Search

in Google Scholar™

Services

Actions (login required)

Edit item

Actions (login required)

Edit item