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Secreted gelsolin inhibits DNGR-1-dependent cross-presentation and cancer immunity

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journal contribution
posted on 12.08.2021, 13:25 by Evangelos Giampazolias, Oliver Schulz, Kok Haw Jonathan Lim, Neil C Rogers, Probir Chakravarty, Naren Srinivasan, Oliver Gordon, Ana Cardoso, Michael D Buck, Enzo Z Poirier, Johnathan Canton, Santiago Zelenay, Stefano Sammicheli, Natalia Moncaut, Sunita Varsani-Brown, Ian Rosewell, Caetano Reis e Sousa
Cross-presentation of antigens from dead tumor cells by type 1 conventional dendritic cells (cDC1s) is thought to underlie priming of anti-cancer CD8+ T cells. cDC1 express high levels of DNGR-1 (a.k.a. CLEC9A), a receptor that binds to F-actin exposed by dead cell debris and promotes cross-presentation of associated antigens. Here, we show that secreted gelsolin (sGSN), an extracellular protein, decreases DNGR-1 binding to F-actin and cross-presentation of dead cell-associated antigens by cDC1s. Mice deficient in sGsn display increased DNGR-1-dependent resistance to transplantable tumors, especially ones expressing neoantigens associated with the actin cytoskeleton, and exhibit greater responsiveness to cancer immunotherapy. In human cancers, lower levels of intratumoral sGSN transcripts, as well as presence of mutations in proteins associated with the actin cytoskeleton, are associated with signatures of anti-cancer immunity and increased patient survival. Our results reveal a natural barrier to cross-presentation of cancer antigens that dampens anti-tumor CD8+ T cell responses.

Funding

Crick (Grant ID: 10019, Grant title: STP BRF - Genetic Modification Service) Crick (Grant ID: 10002, Grant title: STP Bioinformatics & Biostatistics) Crick (Grant ID: 10136, Grant title: Reis e Sousa FC001136) Wellcome Trust (Grant ID: 106973/Z/15/Z, Grant title: WT 106973/Z/15/Z)

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