# Understanding the role of altered lipid metabolism in CD8 T cell exhaustion within the tumor microenvironment

> **NIH NIH F31** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2024 · $48,974

## Abstract

PROJECT SUMMARY/ABSTRACT
The recent successes of checkpoint blockade therapies have highlighted the potential of immunotherapy for
cancer treatment. Still, only about 30% of treatment recipients experience long term tumor regression. Thus,
understanding the mechanisms that drive therapy resistance is essential for improving patient
outcomes. We now understand that the efficacy of immunotherapy depends on the presence and persistence
of functional immune cells within the tumor. Tumor-specific CD8 T cells are activated by tumor antigens and
directly kill tumor cells. However, tumor infiltrating CD8 T cells encounter chronic antigen stimulation and a host
of environmental stressors (e.g hypoxia, nutrient deprivation, etc) that suppress their function. This suppressive
tumor microenvironment ultimately induces an altered CD8 T cell differentiation state called exhaustion,
characterized by reduced effector function, immune inhibitory receptor expression, and a distinct epigenetic and
transcriptional program. Our lab and others have demonstrated that the suppressive microenvironment drives
mitochondrial stress and altered metabolism, which promotes CD8 T cell exhaustion. While we understand that
mitochondrial insufficiency is a driver of CD8 T cell exhaustion, the mechanisms that underly this connection
remain understudied. Interestingly, CD8 T cells accumulate lipids and repress lipolysis as they differentiate
towards an exhausted state. In this study, we aim to understand the impact of increased lipid accumulation on
CD8 T cell differentiation and function. Citrate transported from the mitochondria is converted to acetyl-CoA in
the cytosol, where it acts as a substrate for de novo lipogenesis. Thus, citrate transport connects mitochondrial
metabolism to cytosolic lipid synthesis and accumulation. Preliminary data show that in vitro inhibition of the
mitochondrial citrate transporter (SLC25A1) preserves effector function in chronically stimulated T cells and
reduces lipid content. These data suggest that as exhausted CD8 T cells may reprogram their metabolism to
shuttle citrate from dysfunctional mitochondria, resulting in increased de novo lipogenesis and lipid accumulation
in the cytosol. Thus, we hypothesize that chronically stimulated CD8 T cells inappropriately store
mitochondrial citrate as lipids, which inhibits effector function and promotes differentiation to an
exhausted state. We will test this hypothesis by (1) evaluating the impact of abolishing citrate transport on
carbon utilization and effector function of CD8 T cells within the tumor microenvironment and (2) determining the
role of stored lipids in CD8 T cell function. The insights gained by these studies will help us understand whether
accumulated lipids represent ‘dead weight’ in exhausted CD8 T cells, or whether accumulated lipids represent
an untapped source of fuel that may be the key to their reinvigoration.

## Key facts

- **NIH application ID:** 10996852
- **Project number:** 1F31CA288000-01A1
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Kellie Spahr
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $48,974
- **Award type:** 1
- **Project period:** 2024-07-01 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10996852

## Citation

> US National Institutes of Health, RePORTER application 10996852, Understanding the role of altered lipid metabolism in CD8 T cell exhaustion within the tumor microenvironment (1F31CA288000-01A1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10996852. Licensed CC0.

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