CSIG-39. PROSTAGLANDIN-SCULPTING; REPRODUCTIVE DRIVERS OF THE GBM TUMOR IMMUNE LANDSCAPE

Abstract

Abstract Introduction We have reported that GBM utilize sex-steroids and reproduction-specific proteins to hijack the granting of immune-privilege to male/partner-specific antigens/epitopes. We have extended upon this foundation to examine other examples of immunosuppressive tissue-mimicry mechanisms that GBM deploy. The generation of prostaglandins D2, E2 and F2 and reproductive proteins are used by GBM tumors to activate discrete immune-cell types and to drive vascularization and growth. METHODS Three GBM-transcriptome databases were mined and analyzed utilizing pathway, stratification, correlation and survival analysis. RESULTS PGD2 and PGF2 synthesis is driven by C3AR1 microglial signaling, in response to complement C3a activation by GBM expression of C3 and CFB. PGD2 is expressed in hypoxic tumors and PGF2 is expressed in normoxic ones. PGF2 drives the hematopoietic stem cell angiogenic pathway, via TPBG/CXCL12/CXCR4. This is the primary pathway promoting early placental vascularization and vascular development/repair of mucosal tissues. Microglial synthesized PGD2 drives the CCL5/CCR5 axis, a pathway central to cyclic vascularization of uterine tissues and in wound healing, via VEGFA. Generation of CCL5 also recruits CCR5-positive monocytes, which are then driven into M2-TAM phenotype. CCL5 also recruits and drive myeloid cells into MDSCs. SOX9 drives masculinization of embryonic gonads. GBM expression of SOX9 correlates with seminal heat shock protein expression. These reproductive HSPs are associated with neutrophil generation of PGE2 in GBM tumors, mirroring their role in the semenized female reproductive tract, where they support PGE2 synthesis and aid EGFR driven vascularization CONCLUSIONS The ability of GBM to modulate the anti-tumor response is central to their lethality. The discrete, cell-specific mechanisms revealed will allow personalized medicine using off-the-shelf drug therapy.