Versican proteolysis is associated with robust CD8+ T-cell infiltration in human mismatch repair-proficient and -deficient colorectal cancers

Abstract

Abstract Colorectal cancer (CRC) originates within immunologically complex microenvironments. To date the benefits of immunotherapy have been modest except in neoantigen-laden mismatch repair (MMR)-deficient tumors. Approaches to enhance tumor-infiltrating lymphocytes in the tumor bed may substantially augment clinical immunotherapy responses. We recently reported that proteolysis of the tolerogenic matrix proteoglycan versican (VCAN), in myeloma tumors, generates a bioactive fragment, versikine, with putative immunostimulatory activities. We show that VCAN proteolysis strongly correlated with CD8+ T-cell infiltration in CRC. Tumors displaying active VCAN proteolysis and low total VCAN were associated with robust (10-fold) CD8+ T-cell infiltration. The correlation between VCAN proteolysis and CD8+ T-cell infiltration was maintained in MMR-proficient and -deficient CRCs. Tumor-intrinsic WNT pathway activation was associated with CD8+ T-cell exclusion and correlated with VCAN accumulation. Our findings indicate VCAN proteolysis may shape CRC immune contexture and provide a rationale for testing VCAN proteolysis as a predictive and/or prognostic immune biomarker. Therapeutic manipulation of the VCAN-versikine axis may augment immunotherapy efficacy against CRC.