Abstract
SummaryCross-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.
Highlights
Type 1 conventional dendritic cells are indispensable for effective anti-tumor immunity (Wculek et al, 2020)
SGSN inhibits DNGR-1 binding to F-actin DNGR-1 triggering by F-actin is potentiated by actin-binding proteins (ABPs) such as myosin II (Schulz et al, 2018)
We wondered whether other ABPs might act instead as inhibitors of DNGR-1
Summary
Type 1 conventional dendritic cells (cDC1s) are indispensable for effective anti-tumor immunity (Wculek et al, 2020). The key role of cDC1s in anti-tumor immunity is in part attributed to their ability to transport tumor antigens to draining lymph nodes and prime cancer-specific CD8+ T cells (Alloatti et al, 2017; Broz et al, 2014; Roberts et al, 2016; Salmon et al, 2016; Spranger et al, 2017; Theisen et al, 2018) This requires the acquisition of those antigens from tumor cells and their subsequent presentation by MHC class I molecules, a process termed cross-presentation. The mechanisms by which cDC1s acquire tumor antigens for cross-presentation remain unclear, and it is not known whether interference with this process can constitute a means of cancer immune evasion
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