Prognostic implications of tumor-infiltrating FoxP3+ regulatory T cells and CD8+ cytotoxic T cells in microsatellite-unstable gastric cancers

Abstract

Microsatellite instability (MSI)-high gastric cancers (GC) have better prognosis and higher levels of tumor-infiltrating lymphocytes (TIL) compared with MSI-low or MSI-stable GCs. TILs are part of the adaptive immune response against tumor growth and are associated with improved prognosis in GCs. The aim of this study was to investigate the prognostic significance of CD8+ and FoxP3+ TILs in MSI-high GCs and their relationships with various clinicopathologic characteristics. Intratumoral intraepithelial CD8+ and FoxP3+ TILs were assessed in 99 cases of MSI-high GCs using a computerized image analysis system. TILs were grouped into low- and high-density groups and were analyzed for their relationships with clinicopathologic parameters. A low density was closely associated with a higher TNM stage (P = .040) and invasion depth (P = .044) and more frequent lymphatic and vascular invasion (P = .033 and .015, respectively). GCs with high-density CD8+ or FoxP3+ TILs showed significantly higher overall survival rates than those of GCs with low-density CD8+ or FoxP3+ TILs (P = .017 and .013, respectively, Kaplan-Meier test). In multivariate survival analysis, a high density of FoxP3+ TILs was significantly associated with improved overall survival (P = .027; hazard ratio, 0.269), and the combinatorial status of CD8+ and FoxP3+ TIL density was an independent prognostic factor (P = .003). Our results demonstrate that higher densities of both intratumoral CD8+ and FoxP3+ TILs are associated with good prognosis, suggesting a synergistic activity of these 2 subsets that can be used as an independent prognostic factor in MSI-high GCs.

Keywords: Gastric cancer; Microsatellite instability; Tumor infiltrating lymphocytes.