Stromal Remodeling Regulates Dendritic Cell Abundance and Activity in the Tumor Microenvironment

Overview

Journal Cell Rep

Publisher Cell Press

Specialties Biology
Cell Biology
Molecular Biology

Date 2022 Aug 17

PMID 35977482

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

Affiliations

Soon will be listed here.

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.

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