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

Therapeutic activation of tumor tertiary lymphoid structures (TLS) remains an ongoing challenge. Research has shown that proteolysis of the proteoglycan versican (VCAN) in tumor tissues is associated with increased T-cell inflammation and tumor T-cell infiltration. A study on human metastatic colorectal cancer found that the rate of VCAN proteolysis prospectively predicted outcomes after checkpoint inhibition immunotherapy, with a 100% overall survival rate in the group with high VCAN proteolysis at a median follow-up of 4.1 years.

The study further reveals that VCAN proteolysis occurs in CXCL13-replete germinal center light zones of secondary lymphoid tissue, while inducible VCAN proteolysis is localized in CXCL13-rich tumor stromal niches. The VCAN matrikine, versikine, activates CD11b+ dendritic cells (DC) and expands cDC1, which organizes TLS-archetypal triad hubs.

In cases where VCAN is depleted, versikine-conditioned DC engage progenitor-exhausted CD8+ T-cells (Tpex) and Tpex-supporting, Th1-polarized CD4+ follicular-helper T-cells. On the other hand, excess unproteolyzed VCAN promotes DC-Treg crosstalk and Tpex loss from dysfunctional triads.

The research suggests that therapeutic activation of versikine (mRNA/protein) can eradicate experimental tumors that exhibit a weak VCAN-proteolysis state, which is present in 60-73% of human colorectal cancers. This discovery highlights the co-option of a matrix-processing step from normal germinal center biology and wound-repair processes in tumor lymphoneogenesis, with both prognostic and therapeutic implications.