# Glycolysis and Glutaminase in CD8 T cell differentiation and anti-tumor immunity

> **NIH NIH F30** · VANDERBILT UNIVERSITY · 2021 · $47,980

## Abstract

Summary
Immunotherapy has transformed cancer treatment and improved clinical outcomes, but it does not cure most
patients. Treatments such as anti-PD1 monoclonal antibodies and chimeric antigen receptor (CAR) T cells
function by boosting the activity of cancer-specific interferon gamma-producing Th1 CD4 T cells and
cytotoxic CD8 T cells (CTL). Increased effector function, however, must be balanced with the ability of anti-
cancer T cells to persist long-term. A key goal of immunotherapy is to enhance effector function while
maintaining T cell longevity and memory. It is now clear from work in the Rathmell lab that effector T cells
utilize high rates of glycolysis while memory cells utilize mitochondrial pathways. Here I propose to test cell
metabolism as a means to enhance both effector and memory T cell populations in immunotherapy. T cells
radically alter their metabolism upon activation and increase glycolysis and glutamine oxidation
(glutaminolysis) to support differentiation, effector function, and eventual generation of long-term memory that
depend on mitochondria. Modulation of T cell glutamine metabolism may augment the efficacy of
immunotherapy by enhancing both T cell effector function or memory capacity. The Rathmell Lab has shown
that the metabolic program aerobic glycolysis is essential for effector T cell (Teff) function in inflammation and
in tumors. Glutaminolysis complements glycolysis to fuel T cells by converting glutamine to the tricarboxylic
acid cycle intermediate alpha-ketoglutarate (aKG). Using a conditional knockout of the glutaminolysis enzyme
Glutaminase (GLS), which converts glutamine to glutamate, and an inhibitor of GLS that is currently in clinical
trials as an anti-cancer agent, we have found that inhibition of GLS leads to a compensatory increase in
glycolysis that enhances Th1 and CTL Teff function and differentiation. In addition to increasing effector
function, however, I found that GLS inhibition also increases expression of inhibitory receptors, and chronic
GLS deficiency ultimately suppresses T cells. In contrast, transient GLS inhibition enhanced Teff function while
also priming mitochondrial metabolism for a memory-like differentiation, and led to improved T cell persistence
in vivo. In this proposal, I will test the hypothesis that transient GLS inhibition can augment Teff function and
maintain T cell survival and memory to boost anti-cancer immunotherapy efficacy, whereas chronic GLS
inhibition will drive compensatory glycolysis, terminal Teff differentiation, and exhaustion. I will: (1) Test how
transient versus chronic GLS inhibition affects CTL fate by determining differences in memory T cell formation,
assessing the contribution of compensatory glycolysis to Teff phenotypes, and establishing the mitochondrial
consequences of GLS inhibition; and (2) Test the effect of GLS inhibition on the immunotherapy efficacy of
CD19-targeted CAR T cells and anti-PD1 treatment. These studies will demonstrate a new ...

## Key facts

- **NIH application ID:** 10071866
- **Project number:** 5F30CA239367-02
- **Recipient organization:** VANDERBILT UNIVERSITY
- **Principal Investigator:** Matthew Zachary Madden
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $47,980
- **Award type:** 5
- **Project period:** 2020-01-01 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10071866

## Citation

> US National Institutes of Health, RePORTER application 10071866, Glycolysis and Glutaminase in CD8 T cell differentiation and anti-tumor immunity (5F30CA239367-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10071866. Licensed CC0.

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