# Metabolic Reprogramming of Myeloid Cells to Enhance Cancer Immunotherapy

> **NIH NIH F99** · ROSWELL PARK CANCER INSTITUTE CORP · 2024 · $35,292

## Abstract

PROJECT ABSTRACT/SUMMARY
Immunotherapy has revolutionized how oncologists treat cancer patients. One type of immunotherapy includes
immune checkpoint inhibitors (ICIs), such as those that engage PD-1 on cytotoxic CD8+ T cells to bolster their
effector functions. However, in several cancer types, single-agent therapy is moderately effective, but when
combined with standard-of-care (SOC) chemotherapy, the combination regimen improves overall response
rates. Therapeutic efficacy may be hampered by numerous barriers, including the immune suppressive tumor
microenvironment (TME). One major cellular component of the TME includes myeloid-derived suppressor cells
(MDSCs), which correlate with poorer survival outcomes and suppress antitumor activity of CD8+ T cells in
response to these ICIs. To overcome these obstacles of immune suppression, we developed a novel approach
to target MDSC ‘biogenesis’ in the bone marrow to mitigate their production and function, and boost ICI activity
in mouse models of triple-negative breast cancer (TNBC), a cancer type that elicits a robust MDSC response.
We identified a metabolic vulnerability in MDSCs and targeted that dependency using agents known as
dihydroorotate dehydrogenase (DHODH) inhibitors. DHODH inhibitors block de novo pyrimidine metabolism and
are being clinically tested as a therapy in acute myeloid leukemia. We found that combining the DHODH inhibitor,
brequinar (BRQ), with PD-1 blockade significantly reduced tumor growth, and that therapeutic efficacy depended
upon a reduction in MDSC suppressive activity. However, tumors still grew introducing two important gaps. First,
it remains unclear how DHODH blockade ‘reprograms’ MDSC function and, secondly, it remains unclear how
therapeutic efficacy can be further augmented. Regarding the first gap, in Aim 1 of the F99 phase, we will focus
on the unfolded protein response (UPR) based on the rationale that we found that the UPR pathway is one of
the top downregulated pathways in myeloid progenitors that give rise to MDSCs and that prior work in the field
showed that the UPR is a key pathway by which MDSCs mediate their activities, particularly, via the transcription
factor XBP1. Regarding the second gap, we propose to build on a SOC chemo-immunotherapy platform to
augment antitumor responses. Therefore, in Aim 2 of the K00 phase, we will determine whether incorporating
BRQ to a paclitaxel/anti-PD-1 monoclonal Ab regimen, which is clinically used in TNBC, bolsters CD8+ T cell
responses and achieves durable antitumor immunity. Our central hypothesis is that DHODH blockade
reprograms MDSCs toward less immune suppressive states through an XBP1-dependent mechanism in the
UPR pathway. We further hypothesize that MDSC mitigation through this pathway will further sensitize TNBC to
a SOC chemo-immunotherapy regimen. New advances gained from this research have the potential to inform
the clinical design of novel, more effective combination immunotherapies.

## Key facts

- **NIH application ID:** 10984187
- **Project number:** 1F99CA294065-01
- **Recipient organization:** ROSWELL PARK CANCER INSTITUTE CORP
- **Principal Investigator:** Brian George Morreale
- **Activity code:** F99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $35,292
- **Award type:** 1
- **Project period:** 2024-09-01 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10984187

## Citation

> US National Institutes of Health, RePORTER application 10984187, Metabolic Reprogramming of Myeloid Cells to Enhance Cancer Immunotherapy (1F99CA294065-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10984187. Licensed CC0.

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