Objective To analyze the role of C-C motif receptor 5 (CCR5)^＋ tumor-associated macrophages (TAMs) in the immune regulation of gastric cancer.

Methods Four independent cohorts, including three groups of gastric cancer patients from Zhongshan Hospital, Fudan University (448 cases in the radical surgery cohort, 33 cases in the neoadjuvant immunotherapy cohort, and 46 cases in the palliative immunotherapy cohort) and one group of 336 patients from The Cancer Genome Atlas (TCGA) of the gastric cancer database. The infiltration degree of CCR5^＋TAMs in tumor tissues was determined by immunofluorescence, and the correlation with clinical outcomes was analyzed. The phenotype of CCR5^＋TAMs was detected by flow cytometry analysis, and an in vitro fresh tumor tissue culture system was used to evaluate the potential therapeutic effect of blocking CCR5 in gastric cancer.

Results Patients in the CCR5^＋TAMs high infiltration group had shorter overall survival than those in the CCR5^＋TAMs low infiltration group in radical surgery cohort and palliative immunotherapy cohort (P＜0.05). In the neoadjuvant immunotherapy cohort, patients in CCR5^＋TAMs high infiltration group had lower pathologic complete response rate than those in CCR5^＋TAMs low infiltration group (P＜0.05). CCR5^＋TAMs induced CD8^＋T cell exhaustion through the expression of programmed death-ligand 1 (PD-L1) and interleukin-10 (IL-10), thereby facilitating immune escape. In tumors with high infiltration of CCR5^＋TAMs, CCR5 inhibitation effectively reversed the immunosuppressive tumor microenvironment (P＜0.01).

Conclusions The degree of CCR5^＋TAMs infiltration serves as an independent prognostic factor for patients with gastric cancer. These cells contribute to immune escape of tumor via the expression of PD-L1 and IL-10, leading to the exhaustion of CD8^＋T cell. CCR5 blockade therapy might be a potential therapeutic strategy for gastric cancer.