# Role of tumor microenvironment-derived cholesterol in CD8+ T-cell exhaustion

> **NIH NIH R01** · METHODIST HOSPITAL RESEARCH INSTITUTE · 2020 · $425,512

## Abstract

Project Summary
Recently we discovered that cholesterol metabolically reprograms tumor-infiltrating T cells so that they
become exhausted. Our unpublished, preliminary studies showed that tumor tissues have a much higher
cholesterol content compared with normal tissues, and the PD-1high2B4high CD8+ T cells in tumor-infiltrating T
cells have significantly higher cholesterol content than PD-1med2B4med cells, which in turn have significantly
higher cholesterol content than PD-1low2B4low cells in different murine tumor models. The same was observed
in human multiple myeloma and colon tumor samples of. We also showed that the PD-1high2B4high CD8+ T cells
have significantly higher LAG-3 and TIM-3 (other T-cell exhaustion markers) expression than PD-1med2B4med
cells, and the PD-1med2B4med cells have significantly higher LAG-3 and TIM-3 expression than PD-1low2B4low
cells. Consistently, sorted PD-1high2B4high CD8+ T cells displayed much weaker cytolytic activity against target
tumor cells than PD-1med2B4med CD8+ T cells. Adding cholesterol to the culture of tumor-specific CD8+ T cells
upregulated their expression of PD-1 and other exhaustion markers and reduced their cytolytic activity.
Conversely, reducing cholesterol content in sorted PD-1high2B4high tumor-infiltrating CD8+ T cells downregulated
their expression of PD-1 and other exhaustion markers and enhanced their cytolytic activity. Based on these
novel findings, we hypothe size that the tumor and its microenvironment induce effector T -cell exhaustion by
using cholesterol to metabolically reprogram and upregulate the expression of immune inhibitory receptors and
exhaustion markers on CD8+ cells. Aim 1 will determine the mechanisms underlying cholesterol-induced CD8+
T-cell exhaustion, and Aim 2 will reprogram CD8+ T-cell metabolism and/or the tumor microenvironment to
enhance the antitumor effects of tumor-specific CD8+ T cells. Completing this project will give us in-depth
understanding of the mechanisms involved in how tumor -derived cholesterol metabolically repr ograms tumor-
infiltrating T cells so that they become exhausted. Understanding the mechanisms will allow us and others to
identify novel therapeutic targets and develop new methods to improve the efficacy of T cell- or immune
checkpoint blockade-based immunotherapy in cancer.

## Key facts

- **NIH application ID:** 9983645
- **Project number:** 5R01CA239255-02
- **Recipient organization:** METHODIST HOSPITAL RESEARCH INSTITUTE
- **Principal Investigator:** Qing Yi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $425,512
- **Award type:** 5
- **Project period:** 2019-08-01 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9983645

## Citation

> US National Institutes of Health, RePORTER application 9983645, Role of tumor microenvironment-derived cholesterol in CD8+ T-cell exhaustion (5R01CA239255-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9983645. Licensed CC0.

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