TIM-3 expression identifies a distinctive PD-1 follicular helper T cell subset, with reduced interleukin 21 production and B cell help function in ovarian cancer patients.

Follicular helper T (Tfh) cells are critical regulators of immune responses in several human malignancies. Their characteristics in ovarian cancer (OC) patients remain unclear. In this study, the circulating CD4CXCR5 Tfh cells was examined and compared in OC patients and non-cancer (NC) controls. Data showed that the frequency of PD-1 Tfh cells was significantly higher in OC patients than in NC controls. Compared to PD-1 Tfh cells, PD-1 Tfh cells presented higher interleukin (IL)-21 and IL-10 secretion and stronger proliferation. The PD-1 Tfh cells from OC patients presented further increased IL-21 and IL-10 secretion than those from NC controls. When incubated with autologous naive B cells, PD-1 Tfh cells from both OC patients and NC controls presented elevated capacity at inducing Ig secretion. Interestingly, TIM-3 expression was predominantly found in PD-1 Tfh cells. Compared to TIM-3 PD-1 Tfh cells, TIM-3 PD-1 Tfh cells presented significantly lower levels of IL-21 secretion and lower proliferation. In addition, TIM-3 PD-1 Tfh cells presented marked impairment in inducing IgM, IgG, and IgA secretion from B cells. Importantly, in OC patients, the frequencies of PD-1 Tfh cells and TIM-3 PD-1 Tfh significantly enriched in tumor-infiltrating lymphocytes than in peripheral blood. Together, we demonstrated that Tfh cells could be subdivided into distinctive functional subsets based on PD-1 and TIM-3 expressions, and while PD-1 demarcated a potent Tfh subset, TIM-3 seemed to associate with reduced Tfh function.