Giampazolias and Schulz et al. demonstrated that secreted gelsolin (sGSN), a component of plasma actin-scavenging system, dampens DNGR-1-dependent cross-presentation of tumor antigens by cDC1 and suppresses antitumor immunity. Tumor growth was suppressed in sGsn-/- mice bearing several transplantable tumors – especially in those that presented actin cytoskeleton-associated antigens – in a CD8+ T cell-dependent manner. Loss of sGSN increased DNGR-1-dependent, cDC1-mediated T cell cross-priming. Low sGSN expression in patients with increased intratumoral CLEC9A expression or mutations in F-actin-binding proteins correlated with increased survival.
Contributed by Shishir Pant
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.