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

Award Number: R01CA239255
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2019
PERIOD OF PERFORMANCE END DATE: 07/31/2025

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 Our unpublished, preliminary studies showed that tumor tissues have a much higher cholesterol content compared with normal tissues, and the PD-1high2B4high CD8+ T cells in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


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = -$10,691 )
2026	2023	METHODIST HOSPITAL, THE	6670 BERTNER AVE	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	5	12/8/2025	NON-COMPETING CONTINUATION	-$10,691
														Subtotal = -$10,691

Issue Date FY: 2023 ( Subtotal = $417,003 )
2023	2023	METHODIST HOSPITAL, THE	6670 BERTNER AVE	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	5	7/7/2023	NON-COMPETING CONTINUATION	$417,003
														Subtotal = $417,003

Issue Date FY: 2022 ( Subtotal = $417,003 )
2022	2022	METHODIST HOSPITAL, THE	6670 BERTNER AVE	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	4	7/29/2022	NON-COMPETING CONTINUATION	$417,003
														Subtotal = $417,003

Issue Date FY: 2021 ( Subtotal = $425,512 )
2021	2021	METHODIST HOSPITAL, THE	6670 BERTNER AVE	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	3	7/23/2021	NON-COMPETING CONTINUATION	$425,512
														Subtotal = $425,512

Issue Date FY: 2020 ( Subtotal = $425,512 )
2020	2020	METHODIST HOSPITAL, THE	6670 BERTNER AVE	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	2	9/1/2020	NON-COMPETING CONTINUATION	$425,512
2020	2020	METHODIST HOSPITAL, THE	6670 BERTNER AVE	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	001	2	9/3/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $425,512

Issue Date FY: 2019 ( Subtotal = $425,512 )
2019	2019	METHODIST HOSPITAL, THE	6670 BERTNER AVE	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	1	7/25/2019	NEW	$425,512
														Subtotal = $425,512

Grand Total All Awards = $2,099,851

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

Award Number: R01CA239255

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 08/01/2019

PERIOD OF PERFORMANCE END DATE: 07/31/2025

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