Tmic-62. complement factor h is a novel ligand for the inducible t cell co-stimulator and promotes survival of regulatory t cells in the glioma microenvironment

The survival rates of glioma patients have not shown significant improvement in recent years despite aggressive treatment and advancements in immunotherapy. This lack of response to treatment can be attributed in part to the immunosuppressive microenvironment commonly found in gliomas, where regulatory T cells (Tregs) play a critical role in immunologic tolerance. In this study, we aimed to investigate the influence of complement factor H (FH) on Tregs within the glioma microenvironment. Our findings revealed that FH acts as a novel ligand for the inducible T cell costimulator (ICOS). This interaction between FH and ICOS promotes the survival of Tregs. Furthermore, FH enhances the functional capabilities of Tregs that are crucial for modulating the tumor microenvironment. These include the secretion of transforming growth factor beta and interleukin 10, as well as the suppression of effector T cell proliferation. Immunostaining of human and mouse gliomas demonstrated that cancer cells directly produce FH. Additionally, database analysis revealed an association between upregulated FH expression, the presence of Tregs, and poor prognosis in glioma patients. We validated these findings in a glioma mouse model, where knockdown of FH expression showed a clear tendency to prolong survival. Given that the accumulation of Tregs is indicative of a poor prognosis and represents a promising target for therapy, it is crucial to consider FH expression when evaluating the effectiveness of immunotherapies against glioma.