TMIC-02. JUNCTIONAL ADHESION MOLECULE-A (JAM-A) DEFICIENCY DRIVES SEX-SPECIFIC DIFFERENCES IN GLIOBLASTOMA PROGRESSION VIA DIFFERENTIAL MICROGLIA RESPONSES IN THE TUMOR MICROENVIRONMENT

Abstract

Abstract Despite the male preponderance for developing glioblastoma (GBM) and better survival outcomes in females, current treatment paradigms do not account for biological sex as a biological or clinical variable. Sex-specific molecular alterations that drive tumor cell growth and therapy response have been documented, however, sex-specific extrinsic differences in the tumor microenvironment have yet to be identified. Based on well-established sex-specific gene signatures and functional differences in microglia, we interrogated influences of male and female microglia in driving GBM growth. Specifically, manipulation of JAM-A expression, a tight junction protein on microglia, was exploited as a paradigm for determining effects on in vivo syngeneic GBM mouse models. Male and female JAM-A KO mice that received orthotopic injection of syngeneic GBM cells presented differential overall survival distinct from their wildtype counterparts. Wild-type male mice phenocopied human males, presenting shorter overall survival than females, this trend was reversed in JAM-A KO mice. Compared to the other genotypes, female JAM-A KO mice presented the greatest number of phagocytic, tumor-promoting, activated microglia. RNA-sequencing of tumors from JAM-A KO and WT mice revealed that female JAM-A KO mice had increased expression of Ifi202b (interferon activated gene 202b), a member of the Activity-regulated Inhibitor of Death (AID) gene family that contributes to mitochondrial resistance to cellular stress. Ifi202b has a role in sex-specific inflammatory diseases, which is consistent with our observation. Female KO microglia had enhanced Ifi202b expression, along with the secretion of Ifi202b associated cytokines, including interleukin-6. Treatment of wild-type female microglia with a JAM-A function blocking antibody demonstrated an increase in Ifi202b levels, confirming direct regulation of Ifi202b expression by neutralizing JAM-A. While cell intrinsic, sex-specific differences have been reported in GBM, our findings demonstrate that differences in the GBM tumor microenvironment also drive sexually dimorphic tumor growth.