Tumor Matrix Proteoglycan Accumulation and Processing Alter T-cell Effector Function and the Response to...

Versican (VCAN) is an immunoregulatory matrix proteoglycan that, when cleaved, releases an immunostimulatory fragment, versikine. In this study, we evaluate the impact of VCAN on immune surveillance and immunotherapy response in a prospective clinical trial.

T-cell function was assayed in the setting of VCAN. Normal and matched tissues were acquired from 243 patients across colorectal cancer stages. A phase Ib clinical trial enrolled 15 subjects with microsatellite stable oligometastatic colorectal cancer and examined the safety and efficacy of the sequential combination of stereotactic body radiotherapy, pembrolizumab, and resection (NCT02837263). The outcomes were correlated with the VCAN status and circulating immune phenotype by single-cell RNA sequencing.

VCAN significantly accumulates in 59% of colorectal cancers and is heavily proteolyzed [VCAN proteolytic predominant (VPP)] in 27% (40% of oligometastatic colorectal cancers). VCAN decreased CD8+ T-cell trafficking (P < 0.01) and activated CD8+ T-cell effector function [decreased IL2RA (P < 0.05), PD-1 (P < 0.05), and granzyme B (GZMB; P < 0.001)]. The clinical trial met the primary endpoint with a 1-year recurrence-free survival (RFS) of 60%. Of those enrolled, 40% had the VPP phenotype, which was associated with a trend toward improved RFS (P = 0.053), and all are still alive with a median follow-up of 4.1 years. The VPP phenotype was associated with enhanced circulating CD8+ T-cell effector function at baseline, which was further enhanced with study treatment.

VCAN limits T-cell trafficking and effector function, and its proteolysis correlates with an effector phenotype of circulating CD8+ T cells, greater tumor-infiltrating lymphocytes, and improved clinical outcomes with this immunotherapy-based clinical trial treatment.