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Enhancing TIL populations and immunotherapy efficacy in melanoma by modulating fucosylation

Award Number: R01CA241559
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/01/2019
PERIOD OF PERFORMANCE END DATE: 02/12/2025

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Enhancing TIL populations and immunotherapy efficacy in melanoma by modulating fucosylation - PROJECT SUMMARY/ABSTRACT Our immune system is crucial for recognizing and suppressing cancers in the body. Unfortunately, melanomas, one of the most lethal skin cancers, can interact with and inactivate immune cells. Among the most effective anti-melanoma therapies are immunotherapies that reactivate or “train” the anti-tumor activities of immune cells. However, the effectiveness of immunotherapies is currently limited to ~30% of patients. Although the underlying causes are unclear, lack of responsiveness in patients is associated with insufficient infiltration of tumors by immune cells. Thus, studies aimed at elucidating melanoma:immune interactions and increasing the immune infiltration of tumors are required to improve immunotherapies. We discovered a potential way to increase the efficacy of immunotherapies by boosting infiltration of melanomas with tumor-suppressing immune cells using the plant sugar L-fucose. In a process called fucosylation, cells used L-fucose to modify proteins, affecting their maturation/function. We found that fucosylation is generally reduced during melanoma progression in humans, prompting us to test if increasing L- fucose/fucosylation levels in melanomas elicits therapeutically beneficial effects. Simply feeding L-fucose to melanoma-bearing mice reduces tumor growth and metastasis by >50% (Lau et al. Sci Signal 2015). Intriguingly, those smaller tumors contain 10-50 times more tumor-infiltrating lymphocytes (“TIL”) than tumors from mice not fed L-fucose. Genetically increasing the fucosylation of melanoma cells elicits the same effects, suggesting that melanoma fucosylation triggers anti-tumor immunity. We determined that CD4+/CD25- T cells are crucial for L-fucose-triggered recruitment of TILs including CD8+ T, NK, and DCs that suppress tumor growth. We identified the immune-regulating protein HLA-DRB1 as fucosylated, and its expression is crucial for TIL recruitment/tumor suppression, prompting our hypothesis that fucosylation of HLA-DRB1 triggers CD4+/CD25- T cell-mediated TIL recruitment and suppression of melanoma. However, how fucosylation regulates HLA-DRB1 to mediate anti-melanoma immunity, if those effects are due to increased tumor immunogenicity, CD4+/CD25- T cell function, or both, and if L-fucose/fucosylation can enhance immunotherapy efficacy or have prognostic utility is not known. We propose 3 Specific Aims (SAs) to test our hypothesis and address these questions: ·SA1: Determine how fucosylation regulates the localization and immune function of HLA-DRB1 ·SA2: Determine how systemic fucosylation affects CD4+/CD25- T cell biology. ·SA3: Determine if L-fucose/fucosylation enhances anti-PD1/TIL therapy and predicts patient prognosis Our goal is to provide key biological/mechanistic insights into melanoma:immune interactions, which will establish a basis for developing enhanced, fucosylation-based patient stratification and treatment strategies.


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	2023	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 USF MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Cancer Biology Research	000	5	11/21/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2023	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Cancer Biology Research	001	6	8/6/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$116,514
2025	2023	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 USF MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Cancer Biology Research	000	5	8/6/2025	NON-COMPETING CONTINUATION	-$116,514
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $385,581 )
2023	2023	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Cancer Biology Research	000	5	5/26/2023	NON-COMPETING CONTINUATION	$385,581
														Subtotal = $385,581

Issue Date FY: 2022 ( Subtotal = $385,581 )
2022	2022	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Cancer Biology Research	000	4	6/27/2022	NON-COMPETING CONTINUATION	$385,581
														Subtotal = $385,581

Issue Date FY: 2021 ( Subtotal = $457,861 )
2021	2021	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Cancer Biology Research	000	3	5/17/2021	NON-COMPETING CONTINUATION	$457,861
														Subtotal = $457,861

Issue Date FY: 2020 ( Subtotal = $457,861 )
2020	2020	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Cancer Biology Research	000	2	5/21/2020	NON-COMPETING CONTINUATION	$393,450
2020	2020	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Cancer Biology Research	001	2	8/25/2020	SUPPLEMENT FOR EXPANSION	$64,411
														Subtotal = $457,861

Issue Date FY: 2019 ( Subtotal = $382,794 )
2019	2019	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Cancer Biology Research	000	1	5/24/2019	NEW	$382,794
														Subtotal = $382,794

Grand Total All Awards = $2,069,678

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Enhancing TIL populations and immunotherapy efficacy in melanoma by modulating fucosylation

Award Number: R01CA241559

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/01/2019

PERIOD OF PERFORMANCE END DATE: 02/12/2025

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