Myeloid-derived suppressor cell subset heterogeneity drives glioblastoma progression in a sex-dependent manner

Abstract

Abstract Immunosuppression is a major factor facilitating glioblastoma (GBM) progression and therapeutic resistance. We previously demonstrated that myeloid-derived suppressor cells (MDSCs) expand in GBM patients, but the mechanisms by which MDSC subsets promote tumorigenesis remain unknown. Using multiple syngeneic mouse GBM models, we show that monocytic MDSCs (mMDSCs) accumulate in tumors of males and associate with poor prognosis. Consistent with preclinical observations, males, who constitute 60% of GBM patients and have a worse prognosis than females, had significantly more tumor-infiltrating mMDSCs. In contrast, female tumor-bearing mice had a two-fold increase in circulating granulocytic MDSC (gMDSC) frequency, and a high gMDSC gene signature correlated with poor prognosis of female patients. Male-to-female bone marrow transplantation indicated that immune cell-intrinsic discrepancies drive the sex differences in GBM survival. In line with the differential MDSC localization, targeting gMDSCs with anti-Ly6G neutralizing antibodies extended the lifespan of female mice without affecting males. However, mMDSCs were protected from the anti-Ly6C depletion strategy due to their systemic and local proliferation, as indicated by ex vivo Ki-67 staining and subsequently confirmed by gene expression analysis. Drug-prediction using the differential expression profiles and subsequent pre-clinical testing established that mMDSCs can be targeted by chemotherapies, while IL-1 inhibitors are effective against gMDSCs. These findings indicate that MDSC subset variation represents an opportunity for improved immunotherapy efficacy while accounting for sex as a biological variable.