Abstract
BACKGROUND: Within the tumor microenvironment (TME), the association of B lymphocytes (B cells) with prognosis and therapy response in gastric cancer (GC) remains poorly characterized. We investigated the predictive and prognostic value of B cells, including their spatial organization within the TME, in one of the largest multi-cohort studies to date. METHODS: Using CD20 immunohistochemistry, we evaluated B cell density in resection specimens from 977 patients with resectable GC across three cohorts, including the randomized phase III Korean CLASSIC trial. The relationship between CD20 density, clinicopathological characteristics, and overall survival (OS) was analyzed. Digital spatial profiling of 1063 regions of interest from 15 patients was performed to characterize B cell distribution within different regions of interest (ROIs) using the NanoString GeoMx platform. RESULTS: CD20 density was significantly higher in diffuse-type GC compared to intestinal-type (p = 0.000012). Patients with CD20-low diffuse-type GC had the shortest OS in the CLASSIC trial (median OS: 49 vs 62 months, HR: 1.9, 95% CI: 1.2-3.0, p = 0.003) and in a Japanese cohort (median OS: 49 vs 67 months, HR: 2.2, 95% CI: 1.2-4.0, p = 0.011). This survival difference was not seen in patients treated with adjuvant chemotherapy (median OS: 62 vs 63 months, HR: 1.8, 95% CI: 0.88-3.5, p = 0.108). Spatial profiling revealed significant B cell enrichment within tumor ROIs compared to the stroma, particularly in diffuse-type GC. CONCLUSIONS: Low CD20 positivity, especially in diffuse-type GC, is linked to poor prognosis and may identify patients who could benefit from chemotherapy. These findings underscore the role of B cells in GC.