Increased
CCR5
expression in lymphoma cells and
M2
macrophages is associated with poor prognosis in primary intestinal diffuse large B‐cell lymphoma
Wei‐Li Ma, Tsai‐Yun Chen, Pei‐An Fu, Jo‐Pai Chen, Ming Yao, Hsiu‐Po Wang, Been‐Ren Lin, Chung‐Wu Lin, Chia‐Lang Hsu, Chung‐Yu Huang, Ann‐Lii Cheng, Sung‐Hsin Kuo Abstract
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.