# The Role of Metabolite Sensing in T cell Homeostasis and Tumor Immunology

> **NIH NIH F31** · WEILL MEDICAL COLL OF CORNELL UNIV · 2022 · $46,752

## Abstract

Project Summary
The goal of this project is to define the regulatory networks that control the metabolic function of T lymphocytes
under homeostatic conditions and in the context of cancer. Specifically, we aim to identify the differential
mechanisms by which distinct T cell lineages sense and respond to nutrient and metabolite signals at steady
state (Aim 1) and in experimental models of cancer (Aim 2). Tumor-infiltrating T cells adapt to the tumor
microenvironment (TME) by modulating the signaling and epigenetic networks that control their differentiation
and function. In line with this notion, T cells can acclimate to metabolic conditions in the TME by altering
regulatory mechanisms controlling cholesterol and fatty acid transport, synthesis, and catabolism. Critically,
differences in the bioenergetic requirements of antitumor effector T cells and those of suppressive FOXP3+
regulatory T (Treg) may underlie their relative abundance and functionality in the TME. However, the
mechanisms by which these distinct T cell subsets sense and respond to the metabolic status of the tumor are
poorly understood. We hypothesize that under physiologic conditions and in the tumor setting nuclear receptors
serving as sensors of the local metabolic microenvironment can differentially affect the functionality of Treg and
effector T cells. To test this hypothesis, we will use targeted genetic and pharmacologic approaches to assess
the T cell-intrinsic role of a critical regulator of cellular lipid homeostasis, the liver X receptor (LXR), a sterol-
activated nuclear receptor. In preliminary studies, we found that the survival of Treg, but not effector T cells is
critically impaired by loss of a single copy of Nr1h2, the gene encoding b isoform of LXR (LXRb). The relative
sensitivity of Treg cells to Nr1h2 gene dosage leads us to predict that Treg and effector T cells exhibit differential
requirements for LXRb signaling for metabolic fitness. This cell type-specific metabolic vulnerability makes LXRb
a potential target for therapeutic manipulation of Treg cell function in tumors. Moreover, because the balance
between opposing functions of Treg and effector T cells in the TME determines the outcome of the adaptive anti-
tumor response, an understanding of the differential mechanisms by which Treg and effector T cells sense and
respond to environmental cues to direct their metabolic function may provide novel avenues for specific targeting
of these cells in therapeutic settings. Therefore, our research has the potential to improve clinical care by
accelerating the development of novel strategies for immunometabolic intervention in cancer patients.

## Key facts

- **NIH application ID:** 10445240
- **Project number:** 5F31CA254325-03
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Anthony Michaels
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $46,752
- **Award type:** 5
- **Project period:** 2020-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10445240

## Citation

> US National Institutes of Health, RePORTER application 10445240, The Role of Metabolite Sensing in T cell Homeostasis and Tumor Immunology (5F31CA254325-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10445240. Licensed CC0.

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