Provisional extracellular matrix signaling network regulates tumor lymphoneogenesis and response to immunotherapy

Lagal, D. J.; Hong, D.; Papadas, A.; Yacu, G. S.; Geatches, E.; Leschinsky, N.; Huang, Y.; Dou, Y.; Fields, M.; Gibbons, A.; Molina, E.; Pestonjamasp, K.; Toth, P. T.; Cicala, A.; Mamede, J.; Schneider, J.; Matkowskyj, K.; Deming, D. A.; Naik, S.; Asimakopoulos, F. A.

doi:10.64898/2026.09.24.753585

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bioRxiv · 10.64898/2026.09.24.753585

Provisional extracellular matrix signaling network regulates tumor lymphoneogenesis and response to immunotherapy

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Abstract

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.

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Lagal, D. J., Hong, D., Papadas, A., Yacu, G. S., Geatches, E., Leschinsky, N., Huang, Y., Dou, Y., Fields, M., Gibbons, A., Molina, E., Pestonjamasp, K., Toth, P. T., Cicala, A., Mamede, J., Schneider, J., Matkowskyj, K., Deming, D. A., Naik, S., Asimakopoulos, F. A.. 2026-09-29. Provisional extracellular matrix signaling network regulates tumor lymphoneogenesis and response to immunotherapy. https://doi.org/10.64898/2026.09.24.753585

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