Blockade of CCL2 enhances immunotherapeutic effect of anti-PD1 in lung cancer

Myeloid derived suppressor cells (MDSC) play a pivotal role in tumor immune evasion and MDSC levels increased in patients with cancer. Studies confirmed the associations between MDSC and various cytokines in the peripheral blood. However, little is known about the association between parenchymal MDSC subsets and cytokines, or the mechanism drawing MDSC into tumor parenchyma. This study was to analyze the correlation between MDSC subsets and CCL2 level in lung cancer model. G-MDSC and M-MDSC from the blood and parenchyma were analyzed by flow cytometry and western blot in the lung tumor model. CCL2 was detected by ELISA assay, real-time PCR, western blot and flow cytometry. Furthermore, the therapeutic effects of combination treatment combining CCL2 antagonist and anti-PD1 antibody were assessed. Results showed that MDSC subsets had a positive correlation with CCL2, suggesting CCL2 may attract MDSC into the parenchyma. Gene and protein expression of CCL2, as well as the CCL2 surface expression significantly increased in blood and tumor of tumor-bearing mice. Anti-CCL2 treatment decreased G-MDSC and M-MDSC in the periphery and tumor through inhibiting the protein expression of arginase 1 and iNOS. In addition, combination therapy enhanced CD4(+) and CD8(+) T cell infiltration, as well as the production of interferon gamma (IFNγ), and increased the survival time of tumor-bearing mice. Our study provided potential new target to enhance the efficacy of immunotherapy in patients with lung cancer, in addition to elucidate a possible association between MDSC subsets and the cytokine drawing MDSC migration into the tumor tissue.