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Vitamin B6 Modulates NK Cell Metabolism in Pancreatic Cancer

Award Number: R37CA276924
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/05/2023
PERIOD OF PERFORMANCE END DATE: 08/31/2028

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Vitamin B6 Modulates NK Cell Metabolism in Pancreatic Cancer - Project Summary: The poor survival rates in pancreatic ductal adenocarcinoma patients are in part due to poor response to existing therapies. Thus, there is an urgent need to develop novel therapies. NK cell-based therapies present a promising option because NK cells primarily target tumor cells through direct killing or IFN-gamma production and are not dependent on MHC expression. However, in the tumor microenvironment, NK cells directly compete with tumor cells for nutrients to maintain basal cellular metabolism. Of note, cellular metabolic pathways are closely linked with the effector response of NK cells. Tumor-educated NK cells demonstrate increased glycolysis, which potentiates their cytotoxic activity. However, the complete spectrum of metabolic reprogramming in NK cells is not fully understood. Pancreatic tumors are highly glycolytic. The tumor cells exhibit constant high demand for glucose or glutamine to fuel the anabolic needs and exhaust the essential nutrients in the tumor microenvironment milieu. Nutrient starvation triggers metabolic alterations to support proliferation and the aggressive phenotype of pancreatic tumors. Hence, the pancreatic tumor microenvironment displays nutrient paucity, which restricts the metabolic flux in NK cells. Our preliminary data suggest the scarcity of vitamin B6 in NK-tumor cell co-cultures becomes a limiting factor for the anti-tumor response of NK cells against pancreatic tumor cells and organoids. Furthermore, vitamin B6 paucity and glucose-limitation induce metabolic rewiring in NK cells to sustain glycolysis and downstream metabolic pathways. Of note, tumor progression causes a systemic imbalance of vitamin B6. We observed a significant reduction in systemic vitamin B6 metabolites in PDAC patients. Moreover, we demonstrate that pancreatic tumor cells display increased metabolic flux and dependence on metabolic pathways that are dispensable for NK cells, providing a metabolic vulnerability that can be targeted in combination with vitamin B6 supplementation. Taken together, we posit that pancreatic tumor cells exhaust vitamin B6 in the tumor microenvironment milieu, impacting cellular metabolism and inducing NK cell dysfunction. We will examine (Specific Aim 1) the metabolic pathways that favor tumor cell-mediated vitamin B6 exhaustion in the PDAC TME milieu to sustain tumor cell proliferation under nutrient-limiting conditions. In Specific Aim 2, we will investigate the functional significance of vitamin B6-induced metabolic remodeling in NKs that regulate the anti-tumor response of NK cells in 2D cultures, organoids, and orthotopic mouse models. We will also examine the therapeutic potential of targeting the selective metabolic dependencies of tumor cells, in combination with vitamin B6 supplementation, in the context of nutrient limitation in the tumor microenvironment in orthotopic and patient-derived xenograft models (Specific Aim 3). Overall, our study will investigate the metabolic competition between pancreatic cancer cells and NK cells for understanding the selective metabolic vulnerabilities for developing robust NK-based therapies in the long run.


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 = $387,341 )
2026	2026	UNIVERSITY OF OKLAHOMA	865 RESEARCH PKWY STE 560	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Cancer Biology Research	000	4	8/6/2026	NON-COMPETING CONTINUATION	$387,341
														Subtotal = $387,341

Issue Date FY: 2025 ( Subtotal = $387,341 )
2025	2025	UNIVERSITY OF OKLAHOMA	865 RESEARCH PKWY	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Cancer Biology Research	000	3	8/22/2025	NON-COMPETING CONTINUATION	$387,341
														Subtotal = $387,341

Issue Date FY: 2024 ( Subtotal = $367,975 )
2024	2024	UNIVERSITY OF OKLAHOMA	865 RESEARCH PKWY	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Cancer Biology Research	000	2	8/14/2024	NON-COMPETING CONTINUATION	$367,975
														Subtotal = $367,975

Issue Date FY: 2023 ( Subtotal = $398,591 )
2023	2023	UNIVERSITY OF OKLAHOMA	865 RESEARCH PKWY	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Cancer Biology Research	000	1	7/4/2023	NEW	$398,591
														Subtotal = $398,591

Grand Total All Awards = $1,541,248

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Vitamin B6 Modulates NK Cell Metabolism in Pancreatic Cancer

Award Number: R37CA276924

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/05/2023

PERIOD OF PERFORMANCE END DATE: 08/31/2028

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