A matrikine organizes the dendritic cell-T cell triads that build tertiary lymphoid structures

Tertiary lymphoid structures (TLS) predict response to checkpoint inhibition, and conventional dendritic cells (cDC) are required to build and maintain them. What renders a niche permissive for their assembly is unknown: chemokines recruit the cellular constituents but do not specify how they organize. Here we show that the organizing signal is a matrix fragment. Proteolysis of the proteoglycan versican (VCAN) releases the matrikine versikine, constitutively in germinal center light zones and inducibly in tumor stroma. Versikine activates CD11b⁺ cDC and expands cDC1 to assemble TLS-archetypal triads, apposed DC:CD4⁺T:CD8⁺T units. Versikine-conditioned DC engage progenitor-exhausted CD8⁺ T cells (Tpex) and Th1-polarized follicular helper CD4⁺ T cells. Excess unproteolyzed VCAN inverts this toward DC-Treg crosstalk and Tpex loss. Versikine supplied as mRNA or recombinant protein sensitizes refractory tumors to PD-L1 blockade. VCAN proteolysis prospectively predicted outcomes after PD-1 blockade in metastatic colorectal cancer. Matrikines organize chemokine-recruited cells into functional immune niches.

Chemokines recruit the cells of lymphoid tissue; a VCAN-matrikine organizes them.