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

Cell. 2021 Jul 22;184(15):4016-4031.e22. doi: 10.1016/j.cell.2021.05.021. | PubMed

Evangelos Giampazolias¹, Oliver Schulz¹, Kok Haw Jonathan Lim², Neil C Rogers¹, Probir Chakravarty³, Naren Srinivasan¹, Oliver Gordon¹, Ana Cardoso¹, Michael D Buck¹, Enzo Z Poirier¹, Johnathan Canton¹, Santiago Zelenay¹, Stefano Sammicheli¹, Natalia Moncaut⁴, Sunita Varsani-Brown⁴, Ian Rosewell⁴, Caetano Reis E Sousa⁵

1. Immunobiology Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK.
2. Immunobiology Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK; Department of Immunology and Inflammation, Imperial College London, Du Cane Road, London W12 0NN, UK.
3. Bioinformatics and Biostatistics, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK.
4. Genetic Modification Services, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK.
5. Immunobiology Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK. Electronic address: caetano@crick.ac.uk.

Abstract

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.

Presented By Evangelos Giampazolias