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Understanding how metabolic heterogeneity in cancer affects the tumor microenvironment and anti-tumor immunity

Award Number: R01CA240909
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/01/2020
PERIOD OF PERFORMANCE END DATE: 02/28/2025

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Understanding how metabolic heterogeneity in cancer affects the tumor microenvironment and anti-tumor immunity - Project Summary: Metabolic transformation is a hallmark feature of cancer cells that allows sustained anabolic metabolism to fuel cell growth and proliferation, and when distilled to its core, cancer is ultimately a disease of unchecked anabolic metabolism. Yet, it is not well understood how the aberrant metabolic activity of tumor cells affects the function, phenotype and metabolic states of neighboring immune cells in the tumor microenvironment. The development of new immunotherapies that stimulate anti-tumor T cell responses to control or eradicate cancer is a revolutionary and promising area of cancer therapy, but the immunosuppressive nature of the tumor microenvironment remains the biggest obstacle to increasing the frequency of patients that respond to immunotherapy. We propose that a major component dictating whether the tumor microenvironment (TME) is immuno-supportive or immuno-suppressive is the metabolic state of tumor cells. This model is based on the fact that, like tumor cells, tumor infiltrating lymphocytes (TILs) also require high rates of aerobic glycolysis and glutaminolysis to proliferate and perform tumoricidal effector functions. It is well documented that CD8+ T cells are functionally suppressed or “exhausted” in tumors and perhaps a primary source of this suppression is simply nutrient deprivation stemming from competition between metabolically active tumor and immune cells for the same nutrients. This model of a “metabolic tug-of-war” between tumor and immune cells over nutrients such as glucose and glutamine presents an entirely different perspective on how an immunosuppressive TME may form. To bridge this gap in cancer immunology, we will determine how metabolic pathways, particularly those involved in lipid homeostasis, utilized by melanoma and pancreatic ductal adenocarcinoma (PDAC) affect the quality and function of infiltrating immune cells. Specifically, in Aim 1 we will investigate the balance between lipogenesis and lipolysis in tumor cells to determine how this affects the composition of lipids and lipoproteins in the TME and the types of TILs present. We will test if CD8+ TILs metabolically adapt to changes in tumor cell metabolism and learn how this affects their anti-tumor immune response. In Aim 2, we will investigate if TILs respond to hyperlipidemia and Ox-LDL in the TME via upregulation of the transporter CD36 and elucidate how Ox-LDL-CD36 signaling suppresses CD8+ TIL effector functions (this work is the first to explore this pathway in CD8+ T cells to our knowledge). Lastly, we found arachidonic acid (AA) metabolism correlates with TIL infiltration and in Aim 3 we will explore a new model that the balance of PGD2 and PGE2 changes as tumors progress, converting an immuno-supportive TME to one that is more immuno-suppressive. In all three Aims we will target these metabolic pathways to discover novel combinations of therapies that enhance the efficacy of immunotherapies currently in clinical use today. This work has great potential to uncover several new dimensions of immunosuppression in the tumor microenvironment and interventions to stimulate 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: 2025 ( Subtotal = -$13,344 )
2025	2024	SALK INSTITUTE FOR BIOLOGICAL STUDIES, SAN DIEGO, CALIFORNIA, THE	10010 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Cancer Biology Research	000	5	5/1/2025	NON-COMPETING CONTINUATION	-$13,344
														Subtotal = -$13,344

Issue Date FY: 2024 ( Subtotal = $569,307 )
2024	2024	SALK INSTITUTE FOR BIOLOGICAL STUDIES, SAN DIEGO, CALIFORNIA, THE	10010 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Cancer Biology Research	000	5	2/28/2024	NON-COMPETING CONTINUATION	$539,341
2024	2024	SALK INSTITUTE FOR BIOLOGICAL STUDIES, SAN DIEGO, CALIFORNIA, THE	10010 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Cancer Biology Research	002	5	4/18/2024	NON-COMPETING CONTINUATION	$29,966
2024	2023	SALK INSTITUTE FOR BIOLOGICAL STUDIES, SAN DIEGO, CALIFORNIA, THE	10010 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Cancer Biology Research	001	4	3/6/2024	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $569,307

Issue Date FY: 2023 ( Subtotal = $668,375 )
2023	2023	SALK INSTITUTE FOR BIOLOGICAL STUDIES, SAN DIEGO, CALIFORNIA, THE	10010 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Cancer Biology Research	001	4	4/13/2023	SUPPLEMENT FOR EXPANSION	$81,092
2023	2023	SALK INSTITUTE FOR BIOLOGICAL STUDIES, SAN DIEGO, CALIFORNIA, THE	10010 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Cancer Biology Research	000	4	3/1/2023	NON-COMPETING CONTINUATION	$587,283
														Subtotal = $668,375

Issue Date FY: 2022 ( Subtotal = $587,283 )
2022	2022	SALK INSTITUTE FOR BIOLOGICAL STUDIES, SAN DIEGO, CALIFORNIA, THE	10010 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Cancer Biology Research	001	3	5/25/2022	NON-COMPETING CONTINUATION	$47,944
2022	2022	SALK INSTITUTE FOR BIOLOGICAL STUDIES, SAN DIEGO, CALIFORNIA, THE	10010 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Cancer Biology Research	000	3	2/11/2022	NON-COMPETING CONTINUATION	$539,339
														Subtotal = $587,283

Issue Date FY: 2021 ( Subtotal = $599,268 )
2021	2021	SALK INSTITUTE FOR BIOLOGICAL STUDIES, SAN DIEGO, CALIFORNIA, THE	10010 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Cancer Biology Research	000	2	1/27/2021	NON-COMPETING CONTINUATION	$599,268
														Subtotal = $599,268

Issue Date FY: 2020 ( Subtotal = $599,268 )
2020	2020	SALK INSTITUTE FOR BIOLOGICAL STUDIES, SAN DIEGO, CALIFORNIA, THE	10010 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Cancer Biology Research	000	1	2/4/2020	NEW	$599,268
														Subtotal = $599,268

Grand Total All Awards = $3,010,157

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Understanding how metabolic heterogeneity in cancer affects the tumor microenvironment and anti-tumor immunity

Award Number: R01CA240909

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 03/01/2020

PERIOD OF PERFORMANCE END DATE: 02/28/2025

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