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Metabolic barriers to T cell activation in clear cell renal cell carcinoma

Award Number: R01CA217987
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2018
PERIOD OF PERFORMANCE END DATE: 06/30/2025

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Metabolic barriers to T cell activation in clear cell renal cell carcinoma - SUMMARY Exploiting immunity to eliminate cancer cells offers tremendous new therapeutic opportunities, including the widely employed immune checkpoint blockade (ICB) agents. These approaches are challenged, however, by the multitude of mechanisms through which tumors can suppress anti-tumor immunity and render them effective in only a portion of patients. We have shown that effector T cells require high rates of glucose uptake for anabolic metabolism, and it is now apparent that cancer cells and the tumor microenvironment (TME) disrupt anti-tumor immunity in part through metabolic immune suppression. To address this barrier to immunotherapy, we examined tumor infiltrating lymphocytes (TIL) from surgically excised samples of human clear cell Renal Cell Carcinoma (ccRCC), a cancer with moderate rates of ICB response that is characterized by loss of the Von Hippel-Lindau (VHL) tumor suppressor. These tumors allowed us to show that both glucose and glutamine are available in the TME and while glucose metabolism promotes effector T cells, metabolism of glutamine restrains T cell effector function. It is unclear which glutamine-dependent enzymes or metabolites suppress T cells, but we found that Glutaminase-deficiency altered histone methylation and reduced expression of Pik3ip3, a PI3K- inhibitory protein that suppresses PI3K/mTORC1 signaling and production of inflammatory effector cytokines. To further explore mechanisms of T cell suppression by glutamine, we performed an in vivo CRISPR screen in primary TIL and found loss of Glutamine Synthetase among all glutamine-metabolizing enzymes to most effectively increase TIL accumulation. We also directly defined cell type-specific glucose and glutamine usage in the TME using radiolabeled Positron Emission Tomography tracers. In contrast to classic Warburg metabolism, tumor associated macrophages (TAM) were the dominant consumers of glucose, followed by TIL, and cancer cells, which instead preferentially consumed glutamine. Interestingly, loss of Vhl did not increase glucose uptake of RCC cells in vivo but instead increased glucose uptake in TIL and TAM. To explore these pathways in patients undergoing ICB therapy, we next performed high dimensional CyTOF analyses of peripheral blood from a longitudinal cohort of patients before and 3 weeks after start of therapy. This approach specifically identified rare but highly proliferative ICB-responsive CD8 and CD4 T cells with elevated mitochondrial potential. Based on these findings, we hypothesize that RCC genetics drive a metabolically immunosuppressive TME with abundant glutamine that suppresses PI3K signaling to impair T cell effector differentiation and function. We will study primary human ccRCC tumors and mouse RCC models to: (1) Test how nutrients in the ccRCC TME and tumor genetics influence TIL function and metabolism; and (2) Determine how glucose and glutamine metabolism in the TME promote or suppress anti-tumor immunity. Together, these studies will establish mechanisms by which glutamine impairs T cell differentiation and test new potential targets to overcome metabolic immune suppression in the TME to improve anti-tumor immunity.


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 = -$20,900 )
2026	2025	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Cancer Biology Research	000	8	1/30/2026	NON-COMPETING CONTINUATION	-$332,500
2026	2025	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Cancer Biology Research	002	8	2/11/2026	NON-COMPETING CONTINUATION	$0
2026	2025	UNIVERSITY OF CHICAGO	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Cancer Biology Research	001	9	2/2/2026	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$311,600
														Subtotal = -$20,900

Issue Date FY: 2025 ( Subtotal = $527,128 )
2025	2025	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Cancer Biology Research	001	8	5/22/2025	NON-COMPETING CONTINUATION	$52,713
2025	2025	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Cancer Biology Research	000	8	3/18/2025	NON-COMPETING CONTINUATION	$474,415
														Subtotal = $527,128

Issue Date FY: 2024 ( Subtotal = $511,194 )
2024	2024	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Cancer Biology Research	003	7	3/27/2024	NON-COMPETING CONTINUATION	$484,288
2024	2024	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Cancer Biology Research	004	7	4/17/2024	NON-COMPETING CONTINUATION	$26,906
2024	2023	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Cancer Biology Research	002	6	3/25/2024	COMPETING CONTINUATION	$10,999
2024	2023	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Cancer Biology Research	000	6	12/18/2023	COMPETING CONTINUATION	$0
2024	2022	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Cancer Biology Research	001	5	3/25/2024	NON-COMPETING CONTINUATION	-$10,999
														Subtotal = $511,194

Issue Date FY: 2023 ( Subtotal = $553,322 )
2023	2023	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Cancer Biology Research	000	6	2/15/2023	COMPETING CONTINUATION	$553,322
														Subtotal = $553,322

Issue Date FY: 2022 ( Subtotal = $430,452 )
2022	2022	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Cancer Biology Research	001	5	6/13/2022	NON-COMPETING CONTINUATION	$35,142
2022	2022	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Cancer Biology Research	000	5	3/7/2022	NON-COMPETING CONTINUATION	$395,310
														Subtotal = $430,452

Issue Date FY: 2021 ( Subtotal = $439,237 )
2021	2021	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Cancer Biology Research	000	4	3/19/2021	NON-COMPETING CONTINUATION	$439,237
														Subtotal = $439,237

Issue Date FY: 2020 ( Subtotal = $441,879 )
2020	2020	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Cancer Biology Research	000	3	3/3/2020	NON-COMPETING CONTINUATION	$441,879
														Subtotal = $441,879

Issue Date FY: 2019 ( Subtotal = $431,810 )
2019	2019	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Cancer Biology Research	000	2	2/25/2019	NON-COMPETING CONTINUATION	$431,810
														Subtotal = $431,810

Issue Date FY: 2018 ( Subtotal = $459,666 )
2018	2018	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Cancer Biology Research	000	1	3/7/2018	NEW	$459,666
														Subtotal = $459,666

Grand Total All Awards = $3,773,788

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Metabolic barriers to T cell activation in clear cell renal cell carcinoma

Award Number: R01CA217987

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/01/2018

PERIOD OF PERFORMANCE END DATE: 06/30/2025

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