# Role of myeloid-derived suppressor cells in local and systemic immunosuppression in glioblastoma

> **NIH NIH K99** · CLEVELAND CLINIC LERNER COM-CWRU · 2021 · $120,450

## Abstract

PROJECT SUMMARY: Glioblastoma (GBM) is the most common primary malignant brain tumor, with a median
survival of up to 20 months. Males have a 1.6-fold higher incidence of GBM compared to females and worse
disease outcome. Standard-of-care treatment and immunotherapies, which are currently in clinical trials, have
had limited success improving patient outcome. An immunosuppressive microenvironment facilitating tumor
progression and restricting anti-tumor immune response likely underlies therapeutic resistance. Although
myeloid-derived suppressor cell (MDSCs) accumulate in patients with malignancies and play a critical role in the
establishment of this immunosuppressive milieu, the mechanisms by which individual MDSC subsets promote
tumorigenesis remain poorly defined. In pre-clinical models, I demonstrated that monocytic MDSCs (mMDSCs)
infiltrated tumor at higher rates in males, while granulocytic MDSCs (gMDSCs) were more abundant in the
peripheral circulation of females. Furthermore, there were more immunosuppressive myeloid cells in the tumors
of male patients and gMDSC gene signature associated with poor prognosis of female patients. MDSC subset
variation also determined sex-specific therapeutic response in preclinical models, including to fludarabine and
anti-IL-1β. I also established that complement component 1q (C1q) is highly expressed by gMDSCs and elevated
in females. Based on these observations, I hypothesize that MDSC subsets promote GBM progression via
distinct mechanisms in a sex-specific manner and that their targeting will improve the efficacy of T cell-activating
strategies. Specific Aim 1 will test the hypothesis that mMDSCs and gMDSCs have distinct roles in local and
systemic immunosuppression in a sex-specific manner. This aim will investigate the changes in tumor growth,
vascular density and immune activation status by adoptively transferring MDSC subsets and selectively depleting
MDSCs in bone marrow chimeras. Specific Aim 2 will test the hypothesis that the unique gene expression
signatures of MDSC subsets makes them susceptible to distinct drugs that can be combined with checkpoint
modulators. Sub-Aim 2A will examine the efficacy of drug candidates on MDSC activity in vitro and in vivo, while
Sub-Aim 2B will attempt to achieve durable anti-tumor immune response by combining MDSC targeting
strategies with anti-PD-1, anti-CTLA-4 and anti-OX40. Specific Aim 3 will test the hypothesis that gMDSC-
derived C1q promotes MDSC lineage commitment and systemic immunosuppression by evaluating tumor
progression and checkpoint response in the absence of C1q. Sub-Aim 3A will use C1qa knockout bone marrow
and C1q receptor inhibitors to determine MDSC fate. Sub Aim 3B will use pharmacological inhibitors combined
with checkpoint modulators. These studies lay the foundation for my future research program and the
development of novel immunotherapies for GBM by addressing variations in anti-tumor immunity, repurposing
drugs and defining targetab...

## Key facts

- **NIH application ID:** 10125726
- **Project number:** 1K99CA248611-01A1
- **Recipient organization:** CLEVELAND CLINIC LERNER COM-CWRU
- **Principal Investigator:** Defne Bayik Watson
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $120,450
- **Award type:** 1
- **Project period:** 2021-03-01 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10125726

## Citation

> US National Institutes of Health, RePORTER application 10125726, Role of myeloid-derived suppressor cells in local and systemic immunosuppression in glioblastoma (1K99CA248611-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10125726. Licensed CC0.

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