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528 Sexual dimorphism in myeloid-derived suppressor cells promote GBM progression in females via IL-1b
  1. Defne Bayik1,
  2. Yadi Zhou1,
  3. Chihyun Park1,
  4. Chngjin Hong1,
  5. Danielle Silver1,
  6. Dionysios Watson1,
  7. Alice Lo2,
  8. Tae Hyun Hwang1,
  9. Feixiong Cheng1,
  10. Peter Sims3,
  11. Antonio Iavarone3 and
  12. Justin Lathia1
  1. 1Cleveland Clinic, Cleveland, OH, USA
  2. 2Case Western Reserve University, Cleveland, OH, USA
  3. 3Columbia University, New York, NY, USA


Background A potently immunosuppressive tumor microenvironment facilitates progression of glioblastoma (GBM). Immunotherapies have had variable success in improving the outcome of GBM patients, suggesting that there is a need to gain insight into the mechanisms of immunosuppression. Our findings indicated that proliferating monocytic MDSCs (mMDSCs) accumulate in tumors of male mice and patients, while female tumor-bearing mice had an increase in circulating granulocytic MDSC (gMDSC) frequency, and a high gMDSC gene signature correlated with worse outcome of female patients.

Methods To investigate the basis and prognostic value of sex differences in MDSC profile, we analyzed the role of sex hormones, determined gene expression signatures of MDSCs and preclinically tested the therapeutic benefit of candidate drugs predicted to be effective against individual MDSC subsets.

Results In line with the differential MDSC accumulation pattern, targeting the systemic gMDSCs with the anti-Ly6G neutralizing antibody extended the lifespan of female mice without affecting males. These differences were not driven by sex steroids, as castration or ovariectomy failed to alter MDSC subset accumulation patterns in GBM-bearing mice. Drug-prediction algorithms using the differential MDSC gene expression profiles predicted IL-1 inhibitors are effective against gMDSCs. Correspondingly, IL-1β was highly expressed in female but not male gMDSCs. Single-cell sequencing revealed that circulating but not tumor-infiltrating gMDSCs were the primary source of IL-1β and that its neutralization provided a female-specific survival advantage by reducing circulating gMDSCs. This was accompanied by declines in tumor infiltration of microglia, microglia activation status and tumor cell proliferation. In vitro, IL-1β inhibition reduced viability and expression of activation markers by primary microglia.

Conclusions These findings highlight a novel peripheral gMDSC-microglia IL-1β mediated communication axis in female GBM and indicate expression differences in MDSC subsets can be leveraged for improved immunotherapy efficacy in a sex-specific, precision medicine strategy.

This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See:

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