Role And Mechanism Of Follicular Helper T Cells In Colorectal Cancer

Colorectal cancer is a common malignant tumor of the digestive tract,and the pathogenesis is still unclear.Studies have shown that the dysregulation of immune system is closely related to the development of colorectal cancer.Follicular helper T cells(Tfh)are a newly discovered T cell subtypes that exert multiple functions in the immune system.The applicant hypothesizes that Tfh cells have an important impact on the development and progression of colorectal cancer.This topic first explored the role and mechanism of Tfh cells in the regulation of CD8+T cells in colorectal cancer.Secondly,the role and mechanism of Tfh cells in B cells in colorectal cancer were discussed.The study is divided into two parts.1.To explore the role and regulation mechanism of Tfh on CD8+T cells in colorectal cancer.OBJECTIVE:To determine the role of Tfh in CD8+T cells in patients with colorectal cancer and the related regulatory mechanisms.METHODS:The ratio of Tfh cells in colorectal cancer patients was detected by flow cytometry.The expression of PD-1 on Tfh cells was analyzed.The effect of PD-1+Tfh and PD-1-Tfh cells on CD8+T cells was compared.IL-21 secretion levels in Tfh cells were analyzed.RESULTS:The levels of CD4+CXCR5+Tfh cells were significantly upregulated in patients with stage II colorectal cancer,but gradually decreased in patients with stage III and IV.On the other hand,the proportion of PD-1+ cells in CD4+CXCR5+Tfh cells increased with the severity of colorectal cancer patients.In addition,CD4+CXCR5+PD-1-Tfh cells promoted CD 107a expression and IFN-y expression in CD8+T cells.The ability to promote CD8+T cells was depended on the expression of IL-21.Tfh cells in patients with advanced colorectal cancer showed a gradual decrease in the ability to stimulate CD8+T cells and the ability to produce IL-21.Furthermore,tumor cells autologously expressing PD-L1 further inhibited IL-21 expression of PD-1+Tfh cells.CONCLUSION:These data demonstrate that Tfh cells potentiate the effector function of CD8+T cells via an IL-21-dependent pathway.However,this effect of Tfh cells is limited in colorectal cancer patients due to PD-1/PD-L1 mediated inhibition.2.To explore the effect and regulation mechanism of Tfh on B cells in colorectal cancer.OBJECTIVE:To determine the abnormalities and related mechanisms of Tfh-assisted B cells in rectal cancer patients.METHODS:The effect of Tfh cells on B cell activity in colorectal cancer patients was examined by cell co-culture assay.The expression of PD-L1 on B cells was analyzed.The effect of Tfh cells on the proliferation of PD-L1+B cells was detected.RESULTS:The expression of PD-L1 in tumor infiltrating B cells was significantly higher than that in peripheral blood B cells from the same patient.STAT1 and STAT3 inhibition significantly down-regulated the expression of PD-L1 in stimulated B cells.CpG-stimulated peripheral blood B cells can inhibit IFN-y expression and proliferation of CD8+T cells in a PD-L1-dependent manner.Moreover,tumor infiltrating CD8+T cells incubated with whole tumor infiltrating B cells showed significantly lower IFN-y expression and lower proliferation.In patients with colorectal cancer,Tfh cells presented decreased ability to help B cells secrete immunoglobulin,but effectively stimulate the development of PD-L1+B cells.CONCLUSION:This study showed that the function of Tfh cells in colorectal cancer patients was dysregulated,which upregulated PD-L1+B cells,thereby inhibiting CD8+T cells and causing tumor immune evasion.SIGNIFICANCE OF THE STUDY:The data clarified that colorectal cancer cells may conduct immune evasion through Tfh cell dysfunction.The results also provide a theoretical basis for the development of Tfh-targeted novel immunotherapies.