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. Patients were divided into a discovery (N = 572), internal validation (N = 230), and external validation (N = 232) sets. Tumor microarrays using multiple tumor pieces were made considering intratumoral heterogeneity. A quantitative image analysis was applied. Digital slide images were obtained using the Pannoramic 250 Flash III and analyzed using the CellProfiler v2.2.0. The region of interest was manually selected within the TMA scanned image and extracted as 2 – 10 JPEG images in each case. Single cell segmentation and quantification of staining intensity were performed using a CellProfiler v2.2.0 pipeline. 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 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. Legal entity responsible for the study The authors. Funding Grant (2019IP0408) from the Asan Institute for Life Sciences, Asan Medical Center, Seoul, Korea, and grant (NRF-2017R1D1A1B03033660) from the National Research Foundation of Korea. Disclosure All authors have declared no conflicts of interest.