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Blockade of CCR5-mediated myeloid derived suppressor cell accumulation enhances anti-PD1 efficacy in gastric cancer |
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| Authors: | Liu Yang Bing Wang Jian Qin HengHua Zhou Adhip P. N. Majumdar |
| Affiliation: | 1. Department of Gastroenterology, Shanghai Ninth People’s Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, P.R. China;2. Department of Surgery, Shanghai Ninth People’s Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, P.R. China;3. Department of Pathology, Shanghai Ninth People’s Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, P.R. China;4. Division of Gastroenterology and Department of Internal Medicine, Veterans Affairs Medical Center, Karmanos Cancer Institute, School of Medicine, Wayne State University, Detroit, MI, USA |
| Abstract: | Purpose: Myeloid derived suppressor cells (MDSC) play an important role in tumor immune evasion and its level significantly increased in patients with gastric cancer. Studies confirmed the associations between MDSC and various cytokines in the peripheral blood. However, little is known about the mechanism drawing MDSC into tumor parenchyma. This study was to analyze the correlation between MDSC subsets and CCR5 level in gastric cancer. Materials and methods: G-MDSC and M-MDSC from the peripheral blood and tumor parenchyma were analyzed by flow cytometry. CCR5 ligand CCL5 was detected by ELISA. CCR5 was detected by real-time PCR, western blot and flow cytometry. Furthermore, the therapeutic effects of CCR5 blockade was assessed by the tumor model. Results: CCR5 ligand, gene and protein expression of CCR5, and surface expression of CCR5 significantly increased in blood and tumor of tumor-bearing mice, suggesting MDSC may be attracted into the parenchyma by CCL5/CCR5. Anti-CCR5 treatment decreased G-MDSC and M-MDSC in the periphery and tumor. In addition, combination treatment enhanced CD4+ and CD8+ T cell infiltration and decreased the tumor burden of tumor-bearing mice. Conclusions: This study elucidated a possible association between MDSC subsets and CCR5, in addition to provide a new potential target to enhance the efficacy of immunotherapy in patients with gastric cancer. |
| Keywords: | Myeloid-derived suppressor cells gastric cancer anti-PD1 CCR5 immunotherapy |