# The Role of Glutamine Metabolism in Monocyte-Derived Dendritic Cell Differentiation in the Soft-Tissue Sarcoma Microenvironment

> **NIH NIH F30** · UNIVERSITY OF PENNSYLVANIA · 2021 · $51,036

## Abstract

PROJECT SUMMARY
 Soft-tissue sarcomas (STS) are a diverse and often fatal set of malignancies arising from connective
tissue with a 16% five-year survival rate for metastatic disease, reflecting the need for novel therapeutic
strategies. One approach showing promise against multiple cancers is immune checkpoint blockade. However,
clinical trials of immunotherapy in STS have produced disappointing results, likely due to immunosuppressive
microenvironments characteristic of these diseases. The STS microenvironment is dominated by tumor-
associated macrophages, which largely differentiate from tumor-infiltrating monocytes. These can also
differentiate into anti-tumor monocyte-derived dendritic cells (Mo-DCs) in inflammatory conditions, but Mo-DC
differentiation is inhibited in STS by as-yet unknown factors. We have recently shown that enhanced Mo-DC
differentiation leads to synergy with immune checkpoint blockade. It is therefore critical to discover additional
processes that regulate Mo-DC differentiation in order to improve the efficacy of immunotherapy against STS.
 One such mechanism may depend on glutamine metabolism. Glutamine is utilized as a metabolic fuel
by several immune cell types, as it is involved in generating biosynthetic products via the rate-limiting enzyme
glutaminase, glycosylation of proteins, and activation of mammalian target of rapamycin complex 1 (mTORC1)
mediated signaling pathways. Additionally, recent work has shown that blocking glutamine metabolism can
modulate the anti-tumor activity of tumor-infiltrating immune cells. Using an in vitro model of Mo-DC
differentiation, we found that glutamine deprivation blocked Mo-DC differentiation, surprisingly independent of
glutaminase activity. This finding suggests Mo-DC differentiation requires glutamine flux through separate
pathway(s), such as the hexosamine biosynthetic pathway (HBP) or glutamine-leucine antiport leading to
mTORC1 activation. I hypothesize that glutamine metabolism regulates monocyte-derived dendritic cell
differentiation in the soft tissue sarcoma microenvironment through either the hexosamine
biosynthetic pathway or leucine-dependent mTORC1 activation.
 Aim 1 will identify the mechanisms by which glutamine metabolism regulates the differentiation of
monocytes into Mo-DCs. Isotopic labeling and mass spectrometry will be used to assess the incorporation of
glutamine into downstream metabolites of glutaminase as well as HBP intermediates and export from the cell.
Conditional knockout mice will be used to assess the contributions of HBP flux and mTORC1 activation to Mo-
DC differentiation. Aim 2 will test the impact of glutamine availability and inhibition of glutamine metabolism on
Mo-DC differentiation and function in the STS microenvironment, as well as synergy with immune checkpoint
blockade. Together, these approaches will elucidate the role of glutamine metabolism in Mo-DC differentiation
and function in the STS microenvironment.

## Key facts

- **NIH application ID:** 10313308
- **Project number:** 1F30CA265069-01
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Graham Lobel
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $51,036
- **Award type:** 1
- **Project period:** 2021-07-08 → 2026-07-07

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10313308

## Citation

> US National Institutes of Health, RePORTER application 10313308, The Role of Glutamine Metabolism in Monocyte-Derived Dendritic Cell Differentiation in the Soft-Tissue Sarcoma Microenvironment (1F30CA265069-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10313308. Licensed CC0.

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