# Uncovering the metabolic underpinnings of T cell exhaustion

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2022 · $633,550

## Abstract

PROJECT SUMMARY/ABSTRACT
The successes of immunotherapies like blockade of co-inhibitory `checkpoint' molecules have changed the
treatment paradigm of cancer. However, the fact that robust responses are restricted to a subset of patients
highlights the need to further understand the biology of exhausted T cells: what drives their differentiation,
maintains their dysfunction, and how they may be reinvigorated to eradicate tumor cells. Our lab and others
have revealed that metabolic stress and mitochondrial dysfunction are key drivers in T cell exhaustion, both
from a cell extrinsic and cell intrinsic perspective. We recently reported that mitochondrial stress and reactive
oxygen species (ROS) production, driven to intolerable levels under hypoxic environments in the face of
persistent antigen, was sufficient to deviate cells into a terminally exhausted fate. Antioxidants both
pharmacologic and genetic could bias T cell differentiation away from exhaustion to more functional fates. But precisely how ROS production alters T cell fate and function remains unclear. One of the more intriguing
observations was elevating ROS via mitochondrial dysfunction altered T cell signaling: as peroxide is one of
the more potent inhibitors of tyrosine phosphatases, elevating ROS alone mimicked TCR and other
phosphotyrosine signals. ROS also dramatically reprograms cellular metabolism: by inhibiting aconitase, citrate is driven from the mitochondria where it is converted to acetyl-CoA, acting as a substrate for de novo
lipogenesis. As a result, while exhausted cells possess dysfunctional mitochondria and compete poorly for
glucose, they are loaded with lipid droplets and repress fatty acid oxidiation and lipolysis. While we know that
mitochondrial stress can drive T cells to exhaustion and that terminally exhausted T cells are metabolically
insufficient, the mechanisms that ultimately drive and enforce the phenotype remain unclear. In this Proposal,
we will identify the metabolic underpinnings of T cell exhaustion: how metabolic stress can interfere with
signaling, transcription, and differentiation. AIM 1: Determine how oxidative stress alters T cell signaling
cascades at the level of phosphatase inhibition. ROS play central roles in signaling as inhibitors of tyrosine
phosphatases. We will determine the role of ROS in exhausted T cell function in vivo, and use proteomics and
transcriptomic technologies to identify the phosphorylation cascades susceptible to ROS induction. AIM 2:
Identify how ROS-mediated changes in metabolic flux undermine T cell function. In this Aim, we will explore
the role increased lipid storage plays in T cell function and ask whether these elevated levels of lipids
represent `dead weight' or an untapped fuel source. AIM 3: Define the importance of altered nutrient pathways induced through oxidative stress responses. Our data suggest Slc16a11 similarly supports lactate uptake into exhausted T cells and maintains their dysfunctional state. Usi...

## Key facts

- **NIH application ID:** 10593593
- **Project number:** 1R01AI166598-01A1
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Greg M. Delgoffe
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $633,550
- **Award type:** 1
- **Project period:** 2022-09-19 → 2027-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10593593

## Citation

> US National Institutes of Health, RePORTER application 10593593, Uncovering the metabolic underpinnings of T cell exhaustion (1R01AI166598-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10593593. Licensed CC0.

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