SUMMARY
Stimulatory dendritic cells (SDC), enriched within Batf3-DC (cDC1), engage in productive interactions with CD8+ effectors along tumor-stroma boundaries. The paradoxical accumulation of “poised” cross-presenting Batf3-DC within stromal sheets, distal to tumoral nests, is unlikely to simply reflect passive exclusion away from immunosuppressive tumor cores. Drawing parallels with embryonic morphogenesis, we hypothesized that invasive margin stromal remodeling may generate developmentally conserved cell-fate cues that regulate Batf3-DC behavior. We find that CD8+ T-cells massively infiltrate tumor matrices undergoing proteoglycan versican (VCAN) proteolysis, an essential organ-sculpting modification in development and adult tissue-plane forging. VCAN proteolysis releases a bioactive fragment (matrikine), versikine, that is necessary and sufficient for Batf3-DC accumulation. Versikine does not influence tumor-seeding pre-DC differentiation; rather, it orchestrates a distinctive activation program conferring exquisite sensitivity to DNA-sensing, coupled with survival support from atypical innate lymphoid cells. Thus, homeostatic signals from stroma invasion regulate SDC survival and activity to promote T-cell inflammation.
HIGHLIGHTS
Tumor stroma remodeling generates cross-presenting DC survival and activation cues.
Stromal-activated Batf3-DC are hypersensitive to dsDNA-sensing.
Stromal signals promote atypical innate lymphoid cells (GM-CSFhi/ IFNγlo).
T-cell repriming by stroma-licensed Batf3-DC may overcome exclusion at tumor margins.
Competing Interest Statement
FA and CH are listed as inventors on US patent US20170258898A1: Versikine for inducing or potentiating an immune response. KP reports grants from the National Cancer Institute National Institutes of Health during the conduct of the study; grants and personal fees from AstraZeneca; grants from Kolltan, Roche/Genentech, Boehringer Ingelheim, and Symphogen; and personal fees from Dynamo Therapeutics, Halda, Maverick Therapeutics, and Tocagen outside the submitted work; and a patent for EGFRT790M mutation testing issued, licensed, and with royalties paid from Molecular Diagnostics/Memorial Sloan Kettering Cancer Center.