Inhibition Of Sunitinib On The Expression Of PD-1, PD-L1 And PD-L2 Of Dendritic Cell

Background and ObjectiveRenal cell carcinoma (RCC) is a common urinary system malignant tumor, it is not sensitive to tranditional therapy, the overall survival and prognosis of RCC are poor. With the development of the research on RCC, a new mediation, tyrosine kinase inhibitor, such as sunitinib, significantly improves the overall survival, progression-free survival, and prognosis. However, the incidence of adverse effect was very high in patients who has treated with sunitinib. In addition, the patients with metastatic renal cell carcinoma who treated with targeted drug often develop the treatment resistance. The study of tumor microenvironment found the tumor cells significantly inhibited the function of immune cells in tumor microenvironment, which will lead to the dysfunction and even inactivation of immune cells. In recent years, there were many studies showed it was sensitive to immunotherapy, especially for metastatic renal cell carcinoma. In tumor microenvironment, the high-level expressed PD-L1 on surface of renal carcinoma cells combines with PD-1, which leads to limitation of functions for immune cells, reduction of the anti-tumor immunity, and occurrence of tumor escape. Our study aims to determine whether sunitinib could reduce the expression of programmed death-1 (PD-1), programmed death-1 ligand-1 (PD-L1) and PD-L2 on dendrtic cells and aims to provide theoretical basis for clinical applications of sunitinib in combination with DC on metastatic renal cell carcinoma.Methods DC cells were derived from tibia and thighbone of C57BL/6 mouse and from peripheral blood mononuclear cells from patient with RCC and then were divided into four groups to treated with sunitinib (100, or 200, or 300 ng/mL) and dimethylsulfoxide (DMSO), respectively. After 48 hours, PD-1, PD-L1 and PD-L2 expression level was analyzed by flow cytometry and in the three treatment groups. The stimulating function of DC to T lymphocyte proliferation were evaluated by CCK-8 test.ResultsThe study of DC cells were derived from tibia and thighbone of C57BL/6 mouse: Compared with the control group, the expression of PD-L1 on mature DCs (mDCs) and all DCs [(including mDCs and immature DCs) was significantly down-regulated in sunitinib treatment groups. The PD-L1 expression percentages of imDCs, mDCs, DCs were significantly reduced in sunitinib treatment groups; the percentages of mDCs expressing PD-L2 also dropped in all treatment groups, and the percentages of DCs expressing PD-L2 decreased in 100 and 300 ng/mL sunitinib treatment groups. However, the result of CCK-8 test showed there was no significant difference. The study of DC cells were derived from peripheral blood mononuclear cells from patient with RCC:Compared with the control group, the expression of PD-1 on mDCs was significantly down-regulated in 200 and 300 ng/mL sunitinib treatment groups; the expression of PD-1 on imDCs was significantly down-regulated in 200ng/mL sunitinib treatment group. The expression of PD-L1 on mDCs and imDCs was significantly down-regulated in sunitinib treatment groups. The co-expression of PD-1 and PD-L1 was significantly down-regulated in 200 and 300 ng/mL sunitinib treatment groups. The result of CCK-8 test showed the SI was significant difference between control group and 300 ng/ml sunitinib treatment group.ConclusionsThe expression or percentage of PD-1, PD-L1 and PD-L2 on DC which were derived from peripheral blood mononuclear cells of patients with renal cell carcinoma and tibia and thighbone of C57BL/6 mouse which was treated with suntinib is significantly reduced, and the stimulating function of DC to T lymphocyte proliferation was significantly enhanced. Sunitinib in combination with DC may be an new approach in treating metastatic RCC.