Tumor matrix proteoglycan accumulation and processing alters T cell effector function and the response to immunotherapy in patients with oligometastatic colorectal cancer

Abstract Purpose: Versican (VCAN) is an immunoregulatory matrix proteoglycan that when cleaved releases an immunostimulatory fragment, versikine (Vkine). Here we evaluate the impact of VCAN on immune surveillance and immunotherapy response in a prospective clinical trial. Patients and Methods: T cell function was assayed in the setting of VCAN. Normal and matched tissues were acquired from 243 patients across CRC stages. A phase 1b clinical trial enrolled 15 subjects with microsatellite stable oligometastatic CRC and examined the safety/efficacy of the sequential combination of stereotactic body radiotherapy (SBRT), pembrolizumab, and resection (NCT02837263). The outcomes were correlated with the VCAN status and circulating immune phenotype by scRNAseq. Results: VCAN significantly accumulates in 59% of CRCs and heavily proteolyzed (VCAN proteolytic predominant (VPP)) in 27% (40% of oligometastatic CRCs). VCAN decreased CD8+ T cell trafficking (p0.01) and activated CD8+ T cell effector function (decreased IL2RA (p0.05), PD1 (0.05) and GZMB (p0.001)). The clinical trial met the primary endpoint with a 1-year recurrence free survival of 60%. Of those enrolled, 40% had the VPP phenotype, which was associated with a trend towards 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 enhanced with study treatment. Conclusions: 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.