FOXP3+/CD8+ ratio associated with aggressive behavior in RUNX3‐methylated diffuse esophagogastric junction tumor

Abstract The tumor immune microenvironment is increasingly becoming a key consideration in developing treatment regimens for aggressive cancers, with evidence that regulatory T cells (Tregs) attenuate the antitumor response by interrupting cytotoxic T cells (CD8+). Here, we hypothesized the prognostic relevance of the proportions of Tregs (marked by forkhead box protein 3 [FOXP3]) and CD8+ cells in diffuse, non‐Epstein–Barr virus (EBV)/non‐microsatellite instability (MSI)‐high gastroesophageal adenocarcinomas (GEAs), which are clinically characterized as more aggressive, immunologically inactive tumors as compared with their intestinal counterparts. Cell‐count ratios of FOXP3+/CD8+ expression were calculated at the intratumoral region and invasive margin discretely on digital images from 303 chemo‐naive non‐EBV/non‐MSI‐high esophagogastric junction (EGJ) adenocarcinomas. A significant modifying prognostic effect of tumor histology was observed between 5‐year EGJ cancer‐specific survival and the FOXP3+/CD8+ ratio at the invasive margin in pStage I–III tumors ( p for interaction = 0.022; hazard ratio [HR] = 8.47 and 95% confidence interval [CI], 2.04–35.19 for high ratio [vs. low] for diffuse; HR = 1.57 and 95% CI, 0.88–2.83 for high ratio [vs. low] for intestinal). A high FOXP3+/CD8+ ratio at the invasive margin was associated with RUNX3 methylation ( p = 0.035) and poor prognosis in RUNX3 ‐methylated diffuse histological subtype (5‐year EGJ cancer‐specific survival, 52.3% for high and 100% for low, p = 0.015). Multiomics data from The Cancer Genome Atlas linked CCL28 with RUNX3 ‐suppressed diffuse histological subtypes of non‐EBV/non‐MSI‐high GEA. Our data suggest that a high FOXP3+/CD8+ ratio at the invasive margin might indicate tumor immune escape via CCL28, particularly in the RUNX3 ‐methylated diffuse histological subtype.