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 Our unpublished, preliminary studies showed that tumor tissues have a much higher cholesterol content compared with normal tissues, and the PD-1high2B4high CD8+ T cells in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.

Public Health Relevance

We will determine 1) how cholesterol metabolically reprograms tumor-infiltrating T cells to become exhausted so they are ineffective in killing tumor cells and 2) explore new methods to counteract cholesterol?s effect and so restore T cell function in cancer patients. We hypothesize that reprogramming CD8+ T-cell metabolism and/or reducing cholesterol in the tumor?s microenvironment will effectively restore the antitumor effects of tumor-specific CD8+ T cells. Completing this project will allow us and others to identify novel therapeutic targets and develop new methods to improve the efficacy of current cancer immunotherapies.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA239255-01A1
Application #
9829988
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Mccarthy, Susan A
Project Start
2019-08-01
Project End
2024-07-31
Budget Start
2019-08-01
Budget End
2020-07-31
Support Year
1
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Methodist Hospital Research Institute
Department
Type
DUNS #
185641052
City
Houston
State
TX
Country
United States
Zip Code
77030