A matrikine organizes the dendritic cell–T cell triads that build tertiary lymphoid structures
Year: 2026
Type: preprint
Abstract: Tertiary lymphoid structures (TLS) predict checkpoint-inhibition response, and conventional dendritic cells (cDC) are required to build and maintain them. What licenses tumor niches is not fully understood: chemokines recruit cells but do not specify TLS-archetypal DC:CD4⁺T:CD8⁺T triad composition. We show that the organizing signal is a matrix fragment. Proteoglycan versican (VCAN) proteolysis releases the matrikine versikine constitutively in CXCL13-replete germinal center light zones. In tumors, versikine is released inducibly within CXCL13-rich stromal niches. Versikine activates CD11b⁺ cDC, expands cDC1, and suffices for triad assembly. Versikine-conditioned DC engage progenitor-exhausted CD8⁺ T-cells (Tpex) and Tpex-sustaining, Th1-polarized follicular helper CD4⁺ T-cells. Excess unproteolyzed VCAN inverts this toward DC-Treg crosstalk and Tpex loss. Versikine (mRNA or recombinant protein) plus anti-PD-L1 eradicated experimental tumors reverse-translated to model adverse-prognosis, VCAN-proteolysis-weak patients from a prospective PD-1 blockade trial in oligometastatic colorectal cancer. The extracellular matrix instructs, rather than merely scaffolds, the multicellular units of antitumor immunity.
Authors: Daniel J. Lagal, Duncan Hong, Athanasios Papadas, George S. Yacu, Emma Geatches, Nicholas Leschinsky, Yun Huang, Yaling Dou, Matteo Fields, Alicia Gibbons, Elsa Molina, Kersi Pestonjamasp, Peter T. Toth, Alexander Cicala, Joao Mamede, Jeffrey Schneider, Kristina A. Matkowskyj, Dustin Deming, Surabhi Naik, Fotis Asimakopoulos
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funder: National Cancer Institute
OpenAlex ID: W7214730621