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Mechanisms of Exosome Driven Immunoregulation of Cancer Progression

Award Number: U01CA244452
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/23/2019
PERIOD OF PERFORMANCE END DATE: 08/31/2025

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Mechanisms of Exosome Driven Immunoregulation of Cancer Progression - PROJECT ABSTRACT: Antibodies against the immune checkpoint proteins PD-L1 and PD-1 have revolutionized cancer therapeutics resulting in durable remissions in many patients previous considered incurable. However, a majority of patients remain resistant and cancer types can vary greatly in their response rates. Thus, there is an urgent need to understand the variation in response in order to improve cancer care. This proposal brings together a team of investigators with complementary expertise in basic, translational, and clinical science who share the long-term goal of finding novel approaches to categorize and personalize cancer treatments. Recent results from the investigators suggest a major role for the packaging of immune checkpoint proteins in exosomes underlying the variation in responses to immune checkpoint inhibitors among patients. Specifically, varying amounts of PD-L1 can be trafficked to exosomes, which in turn can act at a distance to suppress anti-tumor T cell function, enabling tumor progression, even in models resistant to anti-PD-L1 treatments. The objective of this proposal is to build on these findings by focusing on the mechanism of exosomal PD-L1 packaging, action, and resistance to therapeutic antibodies. In particular, the proposal will test the overall hypothesis that tumor cells can selectively package PD-L1 into exosomes that suppress T cell priming at distal sights in a fashion that is distinct from the cell-cell interactions of PD-L1 and PD-1 normally seen in the tumor bed. The hypothesis is premised on extensive preliminary data using in vitro and in vivo models showing that the relative fraction of PD-L1 packaged in exosomes versus retained in cells varies between cell lines, that suppression of exosomal PD-L1 can result in long-term systemic anti-tumor immunity, and that exosomal PD-L1 is resistant to anti-PD-L1 antibodies. To test the overall hypothesis, the following aims are proposed: 1) Uncover mechanisms underlying the selective packaging of PD-L1 into exosomes, 2) Evaluate the mechanistic basis of exosomal PD-L1’s impact on systemic immunity, 3) Dissect how exosomal PD-L1 interacts with and regulates its target cells. In aim 1, structure/function and proteomic approaches are proposed to identify the regulators of PD-L1 packaging into exosomes. Furthermore, associations between expression of these factors and resistance to therapy will be evaluated using primary patient samples. In aim 2, mouse-based immunological approaches and patient samples will be used to determine where in the immune axis exosomal PD-L1 functions. Uncovered insights will then be used to develop a novel therapeutic approach to enhance the anti-tumor immune response. In aim 3, microscopy and functional studies in in vitro models along with association studies with patient samples will be used to determine how exosomal PD-L1 interacts with its target cells potentially explaining its resistance to antibodies. The proposal is highly significant in that it is expected to provide new fundamental knowledge that can be used to identify and treat the large fraction of patients resistant to current immune therapies. While this proposal focuses on a subset of cancer models with a particular emphasis on prostate cancer, the paradigms uncovered are expected to be relevant across most if not all tumor types.


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	2019	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	21st Century Cures Act - Beau Biden Cancer Moonshot	000	1	12/12/2025	NEW	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2022	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Trans-NIH Research Support	002	1	7/29/2024	SUPPLEMENT FOR EXPANSION	$0
2024	2021	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Dietary Supplement Research Program	001	1	7/29/2024	SUPPLEMENT FOR EXPANSION	$0
2024	2019	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	21st Century Cures Act - Beau Biden Cancer Moonshot	000	1	7/29/2024	NEW	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $39,956 )
2022	2022	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Trans-NIH Research Support	001	1	8/22/2022	SUPPLEMENT FOR EXPANSION	$39,956
2022	2019	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	21st Century Cures Act - Beau Biden Cancer Moonshot	000	1	10/19/2021	NEW	$0
														Subtotal = $39,956

Issue Date FY: 2021 ( Subtotal = $155,680 )
2021	2021	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Dietary Supplement Research Program	000	1	9/7/2021	SUPPLEMENT FOR EXPANSION	$155,680
														Subtotal = $155,680

Issue Date FY: 2019 ( Subtotal = $3,950,956 )
2019	2019	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	21st Century Cures Act - Beau Biden Cancer Moonshot	000	1	9/23/2019	NEW	$3,950,956
														Subtotal = $3,950,956

Grand Total All Awards = $4,146,592

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Mechanisms of Exosome Driven Immunoregulation of Cancer Progression

Award Number: U01CA244452

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

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

PERIOD OF PERFORMANCE START DATE: 09/23/2019

PERIOD OF PERFORMANCE END DATE: 08/31/2025

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