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Elucidating the role of the Branched Chain Aminotransferases (BCATc and BCATm) as novel metabolic checkpoints of anti-lymphoma T cell immunity

Award Number: R15CA249796
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/16/2021
PERIOD OF PERFORMANCE END DATE: 07/31/2025

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Elucidating the role of the Branched Chain Aminotransferases (BCATc and BCATm) as novel metabolic checkpoints of anti-lymphoma T cell immunity - PROJECT SUMMARY New immunotherapies targeting lymphomas delivered promising results during recent clinical trials. However, these therapies were only effective in a small subset of patients with short periods of remission. The results from these studies suggested the existence of immunosuppression in the tumor microenvironment. Indeed, the lymphoma microenvironment is a very dynamic network between lymphoma cells and non-malignant components that may promote tumor growth and consequently drug resistance. Progress in T cell metabolism has demonstrated that T cells experience a metabolic disadvantage in the tumor microenvironment, which often manifests in T cell exhaustion that jeopardizes their potential to destroy cancer cells. This reveals a critical need to explore new (metabolic) approaches to improve T cell performance. Our research team proposes to target the metabolism of the branched chain amino acids (BCAAs) as a novel metabolic checkpoint of T cell activation in the lymphoma microenvironment. Our rationale stems from the findings that the BCAA, leucine, is indispensable for T cells activation, while BCAA metabolism, initiated by the cytosolic (BCATc) and mitochondrial (BCATm) branched-chain aminotransferases, is a means to direct leucine toward degradation. The objective in this application is to determine whether a loss of expression of BCATc and BCATm is beneficial for the durability and functional integrity of T cells during lymphoma eradication in unique pre-clinical mouse models created in our laboratory. The long-term goal of this application is to provide new means to improve the T cell-mediated immune response and to address the challenges with T cell-driven anti-lymphoma immunotherapy. The central hypothesis is that BCATc, supported by BCATm, serves to provide checkpoint control on T cell function by being a part of a negative feedback loop regulation of T cell activation. Deletion of the BCAT genes from T cells, individually or in combination, may provide a metabolic advantage of T cells allowing them to remain activated and to successfully combat lymphoma growth. To test the central hypothesis, we identified three specific aims: (1) Investigate how the expression of BCATc and BCATm changes upon T cell subset differentiation and whether the BCAT proteins are essential for T cell lineage commitment and function, (2) Determine whether a blockage in the transamination of BCAAs enhances the T cell response to lymphoma tumors, and (3) Investigate whether a loss of expression of BCATc in mouse T cells can overcome the lymphoma resistance to anti-CTLA4 therapy. Completion of this project will not only provide the opportunity to improve the current treatment options for lymphoma patients but will also engage students in pre-clinical cancer studies. The students will highly benefit from acquiring hands-on research experience in cancer, which can be translated into enhanced research skills, scientific reasoning, and better understanding of treatment approaches.


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 = $0 )
2026	2021	DES MOINES UNIVERSITY OSTEOPATHIC MEDICAL CENTER	8025 GRAND AVE	WEST DES MOINES	IA	50266	POLK	USA	Cancer Biology Research	000	1	12/8/2025	NEW	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2021	DES MOINES UNIVERSITY OSTEOPATHIC MEDICAL CENTER	8025 GRAND AVE	WEST DES MOINES	IA	50266	POLK	USA	Cancer Biology Research	000	1	7/10/2024	NEW	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $443,548 )
2021	2021	DES MOINES UNIVERSITY OSTEOPATHIC MEDICAL CENTER	3200 GRAND AVE	DES MOINES	IA	50312	POLK	USA	Cancer Biology Research	000	1	8/16/2021	NEW	$443,548
														Subtotal = $443,548

Grand Total All Awards = $443,548

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Elucidating the role of the Branched Chain Aminotransferases (BCATc and BCATm) as novel metabolic checkpoints of anti-lymphoma T cell immunity

Award Number: R15CA249796

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/16/2021

PERIOD OF PERFORMANCE END DATE: 07/31/2025

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