# Arginine Metabolism Regulates Myeloid Immune Suppression in Glioblastoma

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2022 · $376,000

## Abstract

PROJECT SUMMARY
 Tumor-associated myeloid cells (TAMCs), which consist of tumor associated macrophages and myeloid-
derived suppressor cells, make up a majority of cellular infiltrates in glioma. TAMCs are potently
immunosuppressive, and represent a major barrier to successful immunotherapy. TAMCs highly express
arginase-1 (Arg-1), a catabolic enzyme thought to deplete arginine from the tumor microenvironment. Despite
being a well-known marker of immunosuppressive cells, the metabolic reasons for this choice are not clear.
 Examination of TAMCs phenotype in murine glioma models using RNA-seq, bulk metabolomics, and
carbon-13 arginine flux revealed that two separate pathways of arginine catabolism converge on the generation
of ornithine. Ornithine is the prerequisite substrate for the de-novo generation of polyamines, a group of nitrogen-
rich metabolites with foundational importance to all domains of biology. Importantly, we found that the rate-
limiting step of polyamine generation, ornithine decarboxylase 1 (ODC1), is dramatically upregulated by glioma
infiltrating TAMCS, suggesting de-novo polyamine generation is important for their function. Therefore, the
overall goal of this proposal is to determine how arginine is catabolized into polyamines by TAMCs, and to
determine if inhibition of this metabolic pathway can enhance immunotherapy for glioma.
 Interestingly, we discovered that a second, unstudied metabolic pathway of arginine metabolism, the de-
novo generation of creatine from ornithine, is preferentially utilized by TAMCs in our glioma models. The first aim
of this project is to generate genetically engineered mice (GEM) to determine the role of the de-novo creatine
metabolism in generating immunosuppression in mouse models of glioblastoma. This aim will dissect if creatine
generation is used as a fuel to survive in brain tumors, or is being used to promote immunosuppression.
 Our preliminary experiments suggest that inhibition of the products of arginine metabolism, polyamines,
can perturb TAMC immune suppression. This suggests that polyamines may be critical metabolites for the
functions of TAMCs in brain tumors. Therefore, the second aim of this proposal is to probe the importance of
polyamine metabolism by TAMCs in glioma. We will generate unique conditional knockout animal models to
probe the importance of this pathway in the immunosuppressive functions of TAMCs in glioma.
 The third aim of this project is to determine if targeting of these pathways can be combined with standard
of care for glioma to promote animal survival. First, we will test if a blood-brain-barrier permeable inhibitor of
creatine kinase can be used to stymie TAMCs in glioma. Next, we will use well established inhibitors of polyamine
generation and polyamine uptake in attempts to blunt TAMC mediated immunosuppression in glioma. Lastly, we
will take the clinical inhibitors described above, and determine if they can be used to potentiate checkpoint
immunotherapy ...

## Key facts

- **NIH application ID:** 10331872
- **Project number:** 5R01NS115955-03
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** MACIEJ S LESNIAK
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $376,000
- **Award type:** 5
- **Project period:** 2020-05-01 → 2025-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10331872

## Citation

> US National Institutes of Health, RePORTER application 10331872, Arginine Metabolism Regulates Myeloid Immune Suppression in Glioblastoma (5R01NS115955-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10331872. Licensed CC0.

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