# Investigating Amino Acid Depletion in the Tumor Microenvironment as a Metabolic Immune Checkpoint

> **NIH NIH R01** · SLOAN-KETTERING INST CAN RESEARCH · 2022 · $406,978

## Abstract

PROJECT SUMMARY/ABSTRACT
Activating a patient's immune system to target cancer cells has emerged as an effective therapeutic strategy.
However, many cancer subtypes, including epithelial malignancies such as pancreatic, breast, and colorectal
cancers still respond poorly to existing T-cell therapies. Why immune-based strategies have shown such poor
success in treating these common cancers is not known. In addition to characterizing the inhibitory checkpoints
that restrain T-cell activation, our laboratory previously demonstrated that activated T-cells depend on
extracellular glucose and amino acids to sustain their viability and effector function. Over the last several years,
we have been studying the metabolic properties of the multiple cell types present in the tumor
microenvironment. In addition to tumor cell consumption of glucose and free amino acids, we have found that
tumor-associated fibroblasts can deplete glutamine and other nonessential amino acids from the extracellular
space. In particular, the tumor and fibroblast-dependent depletion of glutamine and cystine (cysteine) makes it
difficult for cells in the tumor microenvironment to maintain protein translation and redox homeostasis. We
have uncovered multiple novel mechanisms by which tumor and stromal cells adapt to amino acid depletion,
including utilizing extracellular proteins as a source of amino acids through macropinocytosis, adaptive
alterations in translation, and activation of the transsulfuration pathway to maintain endogenous cysteine levels
and glutathione levels. Whether tumor-infiltrating immune cells can use any or all of these adaptations is
unknown. Our preliminary evidence suggest that T-cells are unable to maintain their viability and effector
function when depleted of either glutamine and/or cysteine. Therefore, we hypothesize that the tumor
microenvironment drives immunosuppression by depleting these non-essential amino acids. To address this
hypothesis, we propose three Specific Aims: 1) Study whether cancer-associated fibroblasts contribute to
immunosuppression by depleting extracellular free amino acids, 2) Determine the mechanism by which
glutamine depletion impairs anti-tumor immune function, and 3) Examine whether cysteine depletion in tumor-
infiltrating immune cells results in impaired mitochondrial redox homeostasis and/or reduced effector function.
Through these studies, we hope to demonstrate how depletion of glutamine and cysteine drives
immunosuppression within the tumor microenvironment and identify mechanisms by which these amino acids
can be restored to levels that will sustain an anti-tumor immune response.

## Key facts

- **NIH application ID:** 10311105
- **Project number:** 5R01CA248355-02
- **Recipient organization:** SLOAN-KETTERING INST CAN RESEARCH
- **Principal Investigator:** CRAIG B THOMPSON
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $406,978
- **Award type:** 5
- **Project period:** 2020-12-02 → 2025-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10311105

## Citation

> US National Institutes of Health, RePORTER application 10311105, Investigating Amino Acid Depletion in the Tumor Microenvironment as a Metabolic Immune Checkpoint (5R01CA248355-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10311105. Licensed CC0.

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