# Deciphering MDSC function for GBM targeting

> **NIH NIH R01** · CLEVELAND CLINIC LERNER COM-CWRU · 2021 · $434,936

## Abstract

ABSTRACT
Despite a large accumulation of potentially anti-tumoral immune cells, glioblastoma (GBM) sustains its growth
and progression by establishing an immunosuppressive microenvironment. Major clinical efforts in multiple
advanced cancers are aligned toward activating T cells via immune checkpoint inhibition. These strategies are
currently being evaluated for GBM, the most common primary malignant brain cancer, based on success in other
cancers. However, these approaches have not been uniformly successful, likely due to an abundance of
immunosuppressive mechanisms that counteract T cell-activating therapies. Myeloid-derived suppressor cells
(MDSCs) are a heterogeneous population of immunosuppressive cells that accumulate in tumors and are
elevated in patients refractory to immune checkpoint inhibitors. Monocytic (M-) and granulocytic (G-) MDSC
subsets have different mechanisms of immune suppression. We observed that these cells are present within the
GBM microenvironment, with M- and G-MDSCs displaying differential tumor penetration, and are associated
with a poor patient prognosis. MDSCs respond to signals generated by tumor cells, including the secretion of
macrophage migration inhibitor factor (MIF), and both M- and G-MDSCs express MIF receptors, although in
different patterns. These tumor cell-MDSC interactions result in potent immune suppression, and targeting
MDSCs to alleviate this immune suppression confers a survival advantage in pre-clinical GBM models. Given
the high number of immunosuppressive MDSCs present in this tumor, activating T cells alone may not be
sufficient to attenuate tumor growth. However, there may be an opportunity to generate a durable immune
response by concurrently activating T cells in combination with inhibiting MDSCs.
The first translational goal of this project is to assess the individual function of M- and G-MDSCs on GBM growth
and the specific signaling mechanisms they utilize, including the MIF axis. The second translational goal is to
determine the consequence of targeting the MIF signaling axis to attenuate MDSC function in conjunction with
T cell-activating strategies to enhance immune activation to reduce tumor growth. Based on our findings and
new preliminary data, we hypothesize that MDSC subsets respond to MIF signaling differently, resulting in
differential function during GBM growth. We also hypothesize that targeting MDSCs via MIF will reduce immune
suppression and enhance the efficacy of immune activating strategies. Using a newly developed in vitro co-
culture system in combination with MIF pathway knockout mice and blood-brain barrier-penetrating clinically
relevant inhibitors and pre-clinical models, we will test this hypothesis through the following specific aims. Aim 1
will test the hypothesis that MDSC subtypes differentially regulate GBM growth via distinct MIF signaling
responses and immunosuppressive capacities. Aim 2 will test the hypothesis that MIF receptor inhibition will
attenuate ...

## Key facts

- **NIH application ID:** 10223446
- **Project number:** 5R01NS109742-03
- **Recipient organization:** CLEVELAND CLINIC LERNER COM-CWRU
- **Principal Investigator:** Justin D. Lathia
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $434,936
- **Award type:** 5
- **Project period:** 2019-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10223446

## Citation

> US National Institutes of Health, RePORTER application 10223446, Deciphering MDSC function for GBM targeting (5R01NS109742-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10223446. Licensed CC0.

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