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

Therapeutic induction of tumor tertiary lymphoid structures (TLS) remains an unmet need. The proteoglycan versican (VCAN) is a cardinal provisional matrix modification in wound-healing, and its ADAMTS-mediated proteolysis correlates with tumor T-cell inflammation. In human metastatic colorectal cancer, VCAN proteolysis prospectively predicted outcomes after checkpoint inhibition immunotherapy, with 100% overall survival in the intense-proteolysis group at 4.1-year median follow-up.

The new work reports that VCAN undergoes constitutive proteolysis within CXCL13-replete germinal center light zones in secondary lymphoid tissue, whereas inducible VCAN proteolysis localizes within CXCL13-rich tumor stromal niches. The VCAN matrikine versikine activates CD11b+ dendritic cells (DC) and expands cDC1 to organize TLS-archetypal triad hubs.

Under permissive conditions of intact VCAN depletion, versikine-conditioned DC engage progenitor-exhausted CD8+ T-cells (Tpex) and Tpex-supporting, Th1-polarized CD4+ follicular-helper T-cells. Conversely, excess unproteolyzed VCAN favors DC-Treg crosstalk and Tpex loss from dysfunctional triads.

Therapeutic versikine (mRNA/protein) eradicates experimental tumors modeling the VCAN-proteolysis-weak state of 60-73% of human colorectal cancers. Thus, tumor lymphoneogenesis co-opts a matrix-processing step of normal germinal center biology and wound-repair, with prognostic and therapeutic implications.