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Manipulating Lipid Metabolism to Reverse Immune Dysfunction in Solid Cancers

Award Number: R01CA288976
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/03/2024
PERIOD OF PERFORMANCE END DATE: 11/30/2029

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Manipulating Lipid Metabolism to Reverse Immune Dysfunction in Solid Cancers - PROJECT SUMMARY The solid tumor microenvironment (TME) imprints a compromised metabolic state in which tumor infiltrating lymphocytes (TILs) are unable to maintain effective energy synthesis for antitumor function and survival. CD8+ T cells in the TME must catabolize lipids via mitochondrial fatty acid oxidation (FAO) to supply energy in nutrient stress, with T cells enriched in FAO being adept at cancer control. However, endogenous CD8+ TILs and unmodified cellular therapy products fail to sustain bioenergetics in tumors, and the direct molecular mechanism that underlies this failure is unknown. Discovery of a molecular target that enables TILs to utilize effective antitumor metabolism could be implemented immediately to improve clinical immunotherapies. Using RNA- sequencing, lipidomics, confocal imaging, and spectral flow cytometry, we identified that abnormal lipid accumulation was associated with CD8+ TIL metabolic failure across multiple solid tumor types. Acetyl-CoA carboxylase (ACC) is an enzymatic switch that drives lipid accumulation in nutrient-replete states. Under nutrient limitation, ACC is inhibited to enable lipid catabolism through mitochondrial FAO. Paradoxically, we observed that the TME imposes perpetual ACC activity in CD8+ TILs, enforcing lipid storage that directly opposes FAO. Moreover, elevated ACC1 gene expression in tumor samples from melanoma and sarcoma patients was associated with poor survival outcomes. Strikingly, we found that restricting ACC wholly rewired T cell lipid utilization and metabolism, producing a T cell pool enriched in mono and polyunsaturated fatty acids that could be rapidly metabolized for energy, supporting T cell control tumor control. This research program will use genetic mouse models, tumor tissue from cancer patients with advanced disease, pre-clinical CAR-T cell mouse models, and CAR-T products infused into cancer patients to formally test that ACC is a crucial enzymatic switch that profoundly limits antitumor immunity, restricting cancer control. Aim 1 of this proposal will use WT littermate and CD8creACC1f/f mice paired with tumor growth studies, lipidomics, metabolomics, and free fatty acid (FFA) analysis to test that the solid TME engages ACC1 to induce steatosis and loss of antitumor function in endogenous CD8+ TILs. We will validate the clinical relevance of our hypothesis using primary tissue from cancer patients and stored samples from metastatic melanoma patients treated with PD-1 inhibitors. Aim 2 of this proposal will use pre-clinical human and immune-competent CAR-T cell models paired with lipidomics, metabolomics, FFA analysis, and tumor growth studies to test that limiting ACC optimizes CAR-T cell performance in solid tumors. We will validate the clinical relevance of our hypothesis using CAR-T cell products previously infused into cancer patients. Results generated from this proposal will formally establish that the solid TME enforces ACC expression in CD8+ TILs, undermining bioenergetic plasticity by enforcing lipid storage. The data will fill a long-standing gap in knowledge surrounding T cell metabolism in tumors, providing a revolutionary molecular switch able to enhance endogenous and cell-based immunotherapeutic potency.


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 = $469,664 )
2026	2026	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Cancer Biology Research	000	2	12/5/2025	NON-COMPETING CONTINUATION	$469,664
														Subtotal = $469,664

Issue Date FY: 2025 ( Subtotal = $496,391 )
2025	2025	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Cancer Biology Research	000	1	12/3/2024	NEW	$496,391
														Subtotal = $496,391

Grand Total All Awards = $966,055

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Manipulating Lipid Metabolism to Reverse Immune Dysfunction in Solid Cancers

Award Number: R01CA288976

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 12/03/2024

PERIOD OF PERFORMANCE END DATE: 11/30/2029

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