Stromal remodeling regulates dendritic cell abundance and activity in the tumor microenvironment

• Published in: Cell reports (Cambridge) 2022-08, Vol.40 (7), p.111201-111201, Article 111201
• Main Authors: Papadas, Athanasios, Deb, Gauri, Cicala, Alexander, Officer, Adam, Hope, Chelsea, Pagenkopf, Adam, Flietner, Evan, Morrow, Zachary T., Emmerich, Philip, Wiesner, Joshua, Arauz, Garrett, Bansal, Varun, Esbona, Karla, Capitini, Christian M., Matkowskyj, Kristina A., Deming, Dustin A., Politi, Katerina, Abrams, Scott I., Harismendy, Olivier, Asimakopoulos, Fotis
• Format: Article
• Language: English
• Subjects: CD40; cDC1; checkpoint inhibitors; dendritic cells; immunotherapy; proteoglycans; tumor matrix; tumor stroma; versican; versikine
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2022.111201

Stimulatory type 1 conventional dendritic cells (cDC1s) engage in productive interactions with CD8+ effectors along tumor-stroma boundaries. The paradoxical accumulation of “poised” cDC1s within stromal sheets is unlikely to simply reflect passive exclusion from tumor cores. Drawing parallels with embryonic morphogenesis, we hypothesized that invasive margin stromal remodeling generates developmentally conserved cell fate cues that regulate cDC1 behavior. We find that, in human T cell-inflamed tumors, CD8+ T cells penetrate tumor nests, whereas cDC1s are confined within adjacent stroma that recurrently displays site-specific proteolysis of the matrix proteoglycan versican (VCAN), an essential organ-sculpting modification in development. VCAN is necessary, and its proteolytic fragment (matrikine) versikine is sufficient for cDC1 accumulation. Versikine does not influence tumor-seeding pre-DC differentiation; rather, it orchestrates a distinctive cDC1 activation program conferring exquisite sensitivity to DNA sensing, supported by atypical innate lymphoid cells. Thus, peritumoral stroma mimicking embryonic provisional matrix remodeling regulates cDC1 abundance and activity to elicit T cell-inflamed tumor microenvironments. [Display omitted] •Tumor stroma remodeling generates cDC1 survival, recruitment, and activation cues•Stroma-licensed cDC1s overexpress CD40 and are hypersensitive to dsDNA sensing•Stromal remodeling promotes atypical NK cells that are GM-CSFhi IFNγlo•T cell repriming by stroma-licensed cDC1s may overcome exclusion at tumor margins T cell-inflamed tumor microenvironments are a prerequisite for immunotherapy efficacy; however, why some tumors are inflamed and others not remains poorly understood. Papadas et al. link stromal reaction dynamics with T cell-induced inflammation. Peritumoral stroma emulating embryonic provisional matrix remodeling regulates cDC1-NK-CD8+ crosstalk to promote T cell repriming and penetration into tumor nests.