The Expression And Role Of Tim-3 And Its Ligand Galectin-9 In HPV-positive Cervical Cancer Patients

Objective:To investigate the role of Tim-3/Galectin-9 signaling pathway in human papillomavirus(HPV)positive cervical cancer patients.Methods:Expression of Tim-3and Galectin-9 was analyzed with flow cytometry,immunohistochemistry and qRT-PCR.Levels of TGF-β,IL-10,IFN-γ,IL-2,perforin,and granzyme B were detected by Elisa.The effect of Tim-3/Galectin-9 pathway on the function of CD4~+T and CD8~+T cells was verified by blocking experiments in vitro.Results:The expressions of Tim-3 and Galectin-9 in HPV positive cervical cancer tissues were significantly higher than those in other groups(P<0.05).The proportion of Tim-3~+CD4~+T cells and Tim-3~+CD8~+T in HPV positive cervical cancer patients was significantly reduced after surgery(P<0.05).Serum TGF-βand IL-10 levels were positively correlated with the proportion of Tim-3~+Treg cells(r=0.516 and r=0.600),while IFN-γand IL-2 were negatively correlated with Tim-3~+Th1cells proportions(r=-0.592 and r=-0.449).In addition,the proportion of Tim-3~+CD4~+T cells was positively correlated with the proportion of Galectin-9~+monocytes(r=0.508).Survival curve analysis showed that Tim-3~+CD4~+T cells were negatively correlated with patient survival(P<0.05),and the number of Tim-3~+CD4~+T cells was positively all correlated with patients’FIGO stage progression,degree of differentiation,and lymph node metastasis(P<0.05).In vitro experiments showed that by blocking the Tim-3/Galectin-9 pathway,the proliferation of T cells and their ability to express IFN-γ,IL-2,perforin,and granzyme B was significantly restored(P<0.05).Conclusion:In HPV positive cervical cancer patients,Tim-3/Galectin-9 pathway regulates T cells function by inhibiting secretion of cytokines.Tim-3 and Galectin-9 are elevated in HPV positive cervical cancer and associated with disease progression and metastasis.