Immune checkpoint molecule V-set Ig domain-containing 4 (VSIG4) expression is associated with poor prognosis in advanced gastric cancer patients

Abstract

Abstract Background New therapeutic approaches are needed for the treatment of advanced gastric cancer (AGC). V-set Ig domain-containing 4 (VSIG4) is an immune checkpoint molecule that may have prognostic or predictive utility in the treatment of AGC. The aim of this study was to investigate expression of VSIG4 and its clinical significance in AGC and other major cancers. Methods We analyzed VSIG4 expression and its correlation with survival rate in various carcinomas including 1,034 surgically resected AGCs from two academic hospitals. Patients were divided into a discovery (N = 572), internal validation (N= 230), and external validation (N= 232) sets. Results VSIG4-positive AGC tumors were significantly associated with overall survival (OS) (hazard ratio (HR) = 3.02, 95% confidence interval (CI) = 2.32–3.94, P<0.001,) and event-free survival (HR = 2.8, 95% CI=2.18–3.72, P <0.001). These findings was successfully validated in the independent cohorts. VSIG4-positive status was also significantly correlated with low intratumoral CD8+ T-cell infiltration (P = 0.036) and high FoxP3+/CD8+ intratumoral T-cell infiltration ratios (P = 0.016). VSIG4 expression in other cancers was not associated with higher 5-year OS rates (colon, P = 0.459, lung, P = 0.275, kidney, P = 0.121, breast, P = 0.147). Conclusions VSIG4 is an independent prognostic factor in AGC. Notably, VSIG4 expression was significantly associated with low CD8+ T-cell infiltration and high regulatory T cell/CD8+T cell ratios, implying a cancer tolerating immune environment. Our results may be an important basis for future gastric cancer-specific immunotherapeutic drug development.