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

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.

Automated summary

The study reveals that secretion of gelsolin decreases the binding of DNGR-1 to F-actin, leading to reduced cross-presentation of dead cell-associated antigens by conventional dendritic cells. Mice deficient in gelsolin show increased resistance to transplantable tumors and improved responsiveness to cancer immunotherapy. In human cancers, lower levels of intratumoral gelsolin transcripts and mutations in actin cytoskeleton-associated proteins are linked to enhanced anti-cancer immunity and improved patient survival.