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Metabolites regulating macrophage function in colorectal cancer

Award Number: R03CA282844
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2023
PERIOD OF PERFORMANCE END DATE: 06/30/2025

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Metabolites regulating macrophage function in colorectal cancer - ABSTRACT Most colorectal cancer (CRC) patients do not respond to immune checkpoint inhibitor therapies due to poor T cell infiltration and an immune suppressive environment. The pathological characteristics of CRC are unique due to the complex microbiome in the tumor microenvironment. Diverse bacterial species and metabolites in the tumor can alter the activity and function of infiltrating immune cells, regulating the tumor's immune environment. Therefore, understanding how tumor-enriched metabolites change the immune environment is crucial for developing novel microbiota/metabolite intervention approaches. We observed that macrophages resembling an M2-like phenotype are in a higher proportion in CRC samples compared to patient-matched normal tissues. Our metabolomic analysis of CRC tissues showed increases in essential amino acids, which strongly correlate with altered macrophage phenotype. Further, monocytes exposed to tumor-enriched metabolites such as tryptophan and phenylalanine increase markers associated with immunosuppressive macrophages. However, whether microbial-derived metabolites alter macrophage polarization and contribute to immunosuppressive phenotypes, which can influence the immune environment in CRC, remains unknown. We hypothesize that altered enrichment of metabolites in CRC correlates with immunosuppressive macrophages and that critical tumor-enriched metabolites modulate the macrophage phenotypes. In Aim 1, we will assess the impact of tumor-enriched metabolites on macrophage phenotype. In Aim 2, we will functionally validate key metabolites influencing macrophage polarization in CRC organoid coculture models. We will use a metabolite screening approach using human primary peripheral blood mononuclear cells from healthy donors and CRC patients to assess whether tumor-enriched metabolites can promote immunosuppressive macrophage phenotypes. In addition, we will use human microsatellite stable and microsatellite instable CRC organoids cocultured with patients matched undifferentiated monocytes and tumor- enriched metabolites to assess shifts in macrophage subtypes. We will identify critical metabolites that can alter macrophage phenotype and function, contributing to a sustained immunosuppressive tumor environment. Impact. Determining interactions between tumor-enriched metabolites and macrophage phenotype will increase the clinical implications of this study by solidifying the premise that the immune environment can be manipulated by endogenous metabolic regulation.


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	2024	REGENTS OF THE UNIVERSITY OF MINNESOTA	2221 UNIVERSITY AVE SE STE 100	MINNEAPOLIS	MN	55414	HENNEPIN	USA	Cancer Biology Research	000	2	11/17/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $74,274 )
2024	2024	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Cancer Biology Research	000	2	7/1/2024	NON-COMPETING CONTINUATION	$74,274
														Subtotal = $74,274

Issue Date FY: 2023 ( Subtotal = $74,274 )
2023	2023	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Cancer Biology Research	000	1	6/26/2023	NEW	$74,274
														Subtotal = $74,274

Grand Total All Awards = $148,548

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Metabolites regulating macrophage function in colorectal cancer

Award Number: R03CA282844

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/01/2023

PERIOD OF PERFORMANCE END DATE: 06/30/2025

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