# Contribution of sex differences in glioblastoma immune suppression for improved immunotherapy response

> **NIH NIH F32** · CLEVELAND CLINIC LERNER COM-CWRU · 2020 · $29,865

## Abstract

PROJECT SUMMARY/ABSTRACT
Glioblastoma (GBM) is the most lethal primary brain tumor with median survival of up to 20 months despite
aggressive interventions including surgery, radiation, and chemotherapy. An established immunosuppressive
microenvironment facilitating tumor progression is a major factor contributing to the aggressiveness of GBM.
Efforts are underway to develop immunotherapies against GBM, and current strategies primarily focusing on
activation of anti-tumor T cells have thus far been ineffective. This suggests that there is a need to gain
mechanistic insight into the GBM immune architecture, which consists of various immunosuppressive cell types
including tumor-associated macrophages (TAMs) and monocytic-/granulocytic- myeloid-derived suppressor cells
(mMDSCs and gMDSCs). In pre-clinical models, I have demonstrated that the relative frequencies of these
myeloid populations in tumors and the peripheral circulation are different in males, who constitute 60% of GBM
patients and have a worse prognosis, than females. The myeloid compartment is further impacted by the
corticosteroid dexamethasone (DEX), an immunomodulatory drug used clinically to limit cerebral edema but that
dampens radiation and immunotherapy response. Based on these observations, I hypothesize that sexual
dimorphism in anti-tumor immunity determines GBM prognosis and treatment response, which is further altered
by DEX usage. Specific Aim 1 will test the hypothesis that sex differences in GBM immunity contribute to
disease prognosis. Sub-Aim 1A will delineate the role of intrinsic factors versus soluble mediators in the sexual
dimorphism of GBM immune response by investigating the immune infiltration pattern in bone marrow chimeras
and mice treated with sex hormone supplements or antagonists. Sub-Aim 1B will investigate the differential role
of systemic versus local immune suppression between females and males by characterizing the expression
profiles of MDSCs and TAMs and selectively targeting these populations. Specific Aim 2 will test the hypothesis
that inhibiting immunosuppressive myeloid cells mitigates the negative effects of DEX on radiotherapy and
checkpoint inhibitor response. The role of MDSCs/TAMs in DEX-mediated therapeutic resistance will be
examined by depleting these populations during chronic DEX administration prior to or post radiation and
checkpoint inhibition therapy. This project has the potential to develop more effective immunotherapy
approaches by exploring variations in the tumor microenvironment. These insights can inform the development
of novel immunotherapeutics while also improving the implementation of existing treatment modalities by
addressing gaps in our understanding of GBM management strategies. Such results are broadly applicable to
other cancers and can accelerate research to improve patient welfare, leading to advanced treatment
opportunities. The studies outlined in this fellowship will provide me an opportunity to gain experien...

## Key facts

- **NIH application ID:** 9990537
- **Project number:** 5F32CA243314-02
- **Recipient organization:** CLEVELAND CLINIC LERNER COM-CWRU
- **Principal Investigator:** Defne Bayik Watson
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $29,865
- **Award type:** 5
- **Project period:** 2019-08-01 → 2020-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9990537

## Citation

> US National Institutes of Health, RePORTER application 9990537, Contribution of sex differences in glioblastoma immune suppression for improved immunotherapy response (5F32CA243314-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9990537. Licensed CC0.

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