Fn14 Signaling in Glioblastoma-Associated Myeloid Cells Inhibits Th1-Driven Anti-Tumor Immunity 2255143

Abstract

Abstract Introduction Immunotherapy approaches against glioblastoma (GBM) such as immune checkpoint inhibitors (ICI), dendritic cell vaccination, and CAR-T have failed to durably cure most patients. Studies analyzing tumors from ICI responders show that abundance of CD4 and CD8 T cells prior to initiation of therapy predicts responsiveness. Thus, targeting the microenvironment to promote CD4 activity may synergize with ICI. The glioblastoma microenvironment contains high proportions of monocyte-derived macrophages which have potent immunosuppressive capabilities. Characterizing and targeting these immunosuppressive programs is a promising strategy for designing effective combination immunotherapies for glioblastoma patients. Methods We analyzed human glioblastoma snRNAseq datasets to find signaling receptors associated with myeloid immunosuppression and employed murine models of glioblastoma for functional validation. Results By analyzing patient-derived -omics datasets, we identified an understudied TNF-superfamily receptor, Fn14, as being upregulated in glioblastoma-associated myeloid cells with immunosuppressive gene signatures. Using in vitro approaches, we found that Fn14 activation in the tumor microenvironment can drive cytokines implicated in GBM immunosuppression such as IL6, IL1B, and IL8. Thus, Fn14 may serve as a surface marker for microenvironment-remodeling myeloid cells recruited to the tumor from peripheral circulation. Furthermore, in murine models of glioblastoma, we discovered Fn14 KO among glioblastoma-associated myeloid cells increases conventional dendritic cell type 1 (cDC1) and Th1 CD4+ T cell abundance in the tumor microenvironment and significantly prolongs survival. Conclusion These results suggest that blocking Fn14 in glioblastoma-associated myeloid cells can enhance Th1 immunity. Thus, Fn14 may represent a promising dual therapy target. Funding Source NIH Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)