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

Abstract

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.

• Authors: Athanasios Papadas, Gauri Deb, Alexander Cicala, Adam Officer, Chelsea Hope, Adam Pagenkopf, Evan Flietner, Zachary T Morrow, Philip Emmerich, Joshua Wiesner, Garrett Arauz, Varun Bansal, Karla Esbona, Christian M Capitini, Kristina A Matkowskyj, Dustin A Deming, Katerina Politi, Scott I Abrams, Olivier Harismendy, Fotis Asimakopoulos
• Journal: Cell reports (Cell Rep) Vol. 40 Issue 7 Pg. 111201 (08 16 2022) ISSN: 2211-1247 [Electronic] United States
• PMID: 35977482 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.

Chemical References

• Versicans

Topics

• CD8-Positive T-Lymphocytes (metabolism)
• Dendritic Cells (metabolism)
• Humans
• Immunity, Innate
• Lymphocytes (metabolism)
• Neoplasms (pathology)
• Tumor Microenvironment
• Versicans (metabolism)