Cross-presentation of dead cell-associated antigens shapes the neoantigenic landscape of tumor immunity
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Jonathan Lim Oliver Schulz Irene Lobon Tom Castro Dopico Luis Zapata Evangelos Giampazolias Bruno Frederico Carlos Castellanos Michael Buck William Stainier Probir Chakravarty Gavin Kelly Neil Rogers Ana Cardoso Sonia Lee Brian Vash Stephanie Maiocco Raj Mehta Jessica Strid Samra Turajlic Caetano Reis e SousaAbstract
Type 1 conventional dendritic cells (cDC1s) acquire and cross-present tumor antigens to prime CD8⁺ T cells. Whether this selects for specific neoantigens is unclear. DNGR-1 (CLEC9A), a cDC1 receptor for F-actin exposed on dead cells, promotes cross-presentation of cell-associated antigens. Here we show that DNGR-1-deficient mice develop chemically induced tumors more rapidly and at higher incidence, and these are more frequently rejected on transplantation into wild-type recipients. Whole-exome sequencing reveals enrichment of predicted neoantigens derived from mutated F-actin-binding proteins. Consistent with this observation, tethering model antigens to F-actin enhances DNGR-1-dependent cross-presentation. These results suggest that DNGR-1-mediated recognition of F-actin exposed by dead cancer cells favors priming of CD8⁺ T cells specific for cytoskeletal neoantigens, which can then drive immune escape of cancer cells lacking or reverting those mutations. Thus, neoantigen cross-presentation by cDC1 can determine the immune visibility of the tumor mutational landscape and sculpt cancer evolution by immunoediting.
Journal details
Journal
Nature Immunology
Volume
27
Issue number
1
Pages
72-81
Available online
Publication date
Full text links
Publisher website (DOI)
10.1038/s41590-025-02354-w
Figshare
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Europe PubMed Central
41482545
Pubmed
41482545
