腫瘍マトリックスプロテオグリカン蓄積と処理は、乏突起転移性大腸癌患者におけるT細胞エフェクター機能と免疫療法への反応を変化させる

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.

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.

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 (p<0.01) and activated CD8+ T cell effector function (decreased IL2RA (p<0.05), PD1 (<0.05) and GZMB (p<0.001)). 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.

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.