Stromal remodeling regulates dendritic cell abundance and activity in the tumor microenvironment
Athanasios Papadas, Gauri Deb, Alexander Cicala, Adam Officer, Chelsea Hope, Adam Pagenkopf, Evan Flietner, Zachary Morrow, Philip B. 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
Abstract
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.