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Regulation of PD-L1/PD-1 immune checkpoints by cis-interactions

Award Number: R37CA239072
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/01/2019
PERIOD OF PERFORMANCE END DATE: 02/28/2026

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Regulation of PD-L1/PD-1 immune checkpoints by cis-interactions - PROJECT SUMMARY The PD-L1/PD-1 immune checkpoint pathway, consisting of the inhibitory receptor PD-1 on T cells, and its ligand PD-L1 on tumor cells and antigen presenting cells (APCs), is a major mechanism for tumors to escape immune attack. Blocking antibodies of PD-1 and PD-L1 have demonstrated unprecedented clinical activities against an array of human cancers, yet durable benefit is limited to a small subset of patients. Expanding the clinical benefit to a larger population of patients has met critical challenges due to our incomplete understanding of the PD- L1/PD-1 pathway and how their blockade antibodies work. Our long-term goal is to fill these mechanistic gaps through the use of novel, unique and robust approaches. We recently uncovered two novel aspects of PD-L1/PD- 1 signaling. Intracellularly, we showed that the T cell costimulatory receptor CD28 is a primary target of PD-1 associated phosphatases. Extracellularly, we discovered that PD-L1 can be neutralized in cis by PD-1 expressed on the same cells, i.e., APCs. In this proposal, we will integrate and extend these two prior findings to elucidate a poorly defined extracellular crosstalk between PD-L1/PD-1 and CD28 pathways. Our preliminary experiments revealed that the CD28 ligand B7.1 binds and neutralizes PD-L1 in cis, but not in trans. Guided by this new finding, we propose to pursue three specific aims to determine the biochemical and functional consequences of the B7.1/PD-L1 cis-interaction and how this interaction might underlie unreported mechanisms of actions for PD- L1 and PD-1 blockade antibodies. In Aim-1, we will determine whether B7.1 neutralizes the ability of PD-L1 to bind and activate PD-1 through cis-interaction. In Aim-2, we will ask the reciprocal question of whether cis-PD- L1 inhibits the ability of B7.1 to bind and activate CD28. In Aim-3, we will use well-defined co-culture assays and mouse tumor models to determine the effects of PD-1 and PD-L1 blockade antibodies in the context of B7.1/PD- L1 cis-interaction. The key for achieving these goals is to decouple and quantitate cis and trans interaction at the cell-cell interface. To this end, we plan to integrate classical approaches and our recently developed membrane reconstitution, live cell imaging (TIRF) and cell-specific antibody blockade assays. Completion of the project will reveal in-depth insights into the regulatory mechanism of the PD-L1/PD-1 immune checkpoint axis, its crosstalk with the B7/CD28 pathway, and the mechanism of actions of therapeutic antibodies. These mechanistic insights will likely yield novel targets and biomarkers of PD-1 targeted cancer immunotherapy.


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 = $353,926 )
2025	2025	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Cancer Biology Research	002	7	6/25/2025	NON-COMPETING CONTINUATION	$35,391
2025	2025	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Cancer Biology Research	001	7	2/13/2025	NON-COMPETING CONTINUATION	$318,535
2025	2023	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Cancer Biology Research	000	5	1/30/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $353,926

Issue Date FY: 2024 ( Subtotal = $336,567 )
2024	2024	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Cancer Biology Research	001	6	6/18/2024	EXTENSION WITH OR WITHOUT FUNDS	$17,710
2024	2024	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Cancer Biology Research	000	6	2/2/2024	EXTENSION WITH OR WITHOUT FUNDS	$318,857
														Subtotal = $336,567

Issue Date FY: 2023 ( Subtotal = $354,197 )
2023	2023	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Cancer Biology Research	000	5	2/3/2023	NON-COMPETING CONTINUATION	$354,197
														Subtotal = $354,197

Issue Date FY: 2022 ( Subtotal = $399,303 )
2022	2022	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Cancer Biology Research	000	4	3/14/2022	NON-COMPETING CONTINUATION	$325,283
2022	2022	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Cancer Biology Research	001	4	4/19/2022	NON-COMPETING CONTINUATION	$36,142
2022	2022	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Cancer Biology Research	002	4	4/22/2022	NON-COMPETING CONTINUATION	$37,878
														Subtotal = $399,303

Issue Date FY: 2021 ( Subtotal = $361,044 )
2021	2021	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Cancer Biology Research	000	3	2/22/2021	NON-COMPETING CONTINUATION	$361,044
														Subtotal = $361,044

Issue Date FY: 2020 ( Subtotal = $360,281 )
2020	2020	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Cancer Biology Research	000	2	2/4/2020	NON-COMPETING CONTINUATION	$360,281
														Subtotal = $360,281

Issue Date FY: 2019 ( Subtotal = $359,901 )
2019	2019	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR DEPT 621	LA JOLLA	CA	92093	SAN DIEGO	USA	Cancer Biology Research	000	1	2/12/2019	NEW	$359,901
														Subtotal = $359,901

Grand Total All Awards = $2,525,219

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Regulation of PD-L1/PD-1 immune checkpoints by cis-interactions

Award Number: R37CA239072

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 03/01/2019

PERIOD OF PERFORMANCE END DATE: 02/28/2026

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