Increased CCR5 expression in lymphoma cells and M2 macrophages is associated with poor prognosis in primary intestinal diffuse large B-cell lymphoma.

Few studies have evaluated the impact of organ-specific tumor microenvironments (TMEs) on clinical outcomes in diffuse large B-cell lymphoma (DLBCL). This study investigated potential molecular markers, the immune cell composition within the TME, and their associations with clinical outcomes in patients with primary intestinal DLBCL (PI-DLBCL). We initially analyzed RNA expression in tumor cells from 19 patients with PI-DLBCL in the experimental cohort. Candidate biomarkers were then assessed in lymphoma tissue from a total of 48 patients in the same cohort, including the 19 with RNA-expression data, and validated in an independent cohort of 29 patients with PI-DLBCL. Associations between these markers and clinicopathological features, event-free survival (EFS), and overall survival (OS) in the two cohorts were analyzed. In the RNA expression panel, CCL5 expression was higher in patients with advanced-stage PI-DLBCL and was associated with inferior EFS and OS. Its principal receptor, CCR5, expressed in approximately one-third of patients, was associated with lower complete response rates to first-line immunochemotherapy: 50% in the experimental cohort and 10% in the validation cohort and correlated with the 7-year worse OS rate in both the experimental (49.8% versus 71.4%, p = 0.082) and validation (0% versus 76.2%, p < 0.001) cohorts. In both the experimental and validation cohorts, CCR5-positive tumors exhibited decreased CD86-positive (M1-like) and increased CD206-positive (M2-like) macrophage infiltration, consistent with an immunosuppressive TME. Multivariate analyses revealed that CCR5 expression was independently associated with worse EFS (p < 0.001) and OS (p = 0.004) in patients with PI-DLBCL (combined experimental and validation cohorts). CCR5 expression indicates a biologically aggressive subtype of PI-DLBCL with poor clinical outcomes and M2 macrophage-dominant immunosuppression.