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Exploiting the Mechanobiology of PD-1 for Cancer Immunotherapy

Award Number: U01CA250040
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/01/2020
PERIOD OF PERFORMANCE END DATE: 05/31/2025

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Exploiting the Mechanobiology of PD-1 for Cancer Immunotherapy - PROJECT SUMMARY Programmed cell death 1 (PD-1) is one of the key co-inhibitory molecules upregulated upon T cell activation and is a hallmark of T-cell exhaustion. Despite the fact that PD-1 blockade has become a revolutionary strategy in treating cancer and infectious diseases, the mechanobiology of PD-1 has not been studied. This is the gap that tne present Physical Science – Oncology Project (PS-OP) aims to fill. The significance of the PS-OP’s unique mechanobiology angle lies in the therapeutic potential of targeting the mechanoregulation of PD-1 to treat a wide variety of diseases, including melanoma, which is the focus of this PS-OP. The approaches of the PS-OP’s multidisciplinary team combine four physical science (PS) tools with two mouse models of melanoma. They represent the unique strength of the Zhu lab and the Ahmed lab, and enable investigation of PD-1 mechanobiology in silico, in vitro and in vivo. The first PS tool is DNA-based mechanical tension probes (MTP) and tension gauge tethers (TGT) that report and limit, respectively, cell-generated forces on PD-1. The second PS tool is three biomembrane force probe (BFP)-based single-molecule methods that quantify force regulation of in situ PD-1–PD-ligand interactions with concurrent imaging of intracellular signals in single cells. The third PS tool is molecular dynamics (MD) simulations that reveal structural changes of PD-1 in complex with its ligands under force and the bonding dynamics at atomic level. The fourth PS-tool is microfluidic-based devices for cell trapping, stimulation, and analysis. Preliminary studies of the project demonstrate that: 1) cells actively pull on PD-1; 2) force on PD-1 elicits catch bonds to regulate ligand bonding; 3) force induces rearrangement of the PD- 1–PD-L2 binding interface to form new atomic-level interactions; 4) mutating specific amino acids on PD-1 alters its force, catch bond and function; and 5) PD-1’s inhibitory signal suppresses antigen recognition by disrupting the synergy between TCR and CD8 in pMHC binding. These data support the hypothesis that force critically regulates ligand bonding and signaling of PD-1; as such, targeting the PD-1 mechanoregulation may represent a novel approach to immunotherapy. This hypothesis will be tested by three specific aims: 1) Determine the forces on PD-1 and their impact on PD-1 ligand bonding, signaling and function; 2) Modulate T cell function by targeting PD-1 mechanoregulation; and 3) Investigate the therapeutic potential of manipulating PD-1 catch bonds in tumor mouse models. These studies will elucidate the mechanisim of PD-1 signaling, improve one’s understanding of CD8+ T-cell responses to melanoma, and suggest new immunotheraputic strategies to treating cancer.


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: 2024 ( Subtotal = $681,505 )
2024	2024	GEORGIA TECH RESEARCH CORP	926 DALNEY ST NW	ATLANTA	GA	30318	FULTON	USA	Cancer Biology Research	000	5	7/15/2024	NON-COMPETING CONTINUATION	$600,878
2024	2024	GEORGIA TECH RESEARCH CORP	926 DALNEY ST NW	ATLANTA	GA	30318	FULTON	USA	Cancer Biology Research	001	5	7/16/2024	SUPPLEMENT FOR EXPANSION	$80,627
														Subtotal = $681,505

Issue Date FY: 2023 ( Subtotal = $775,247 )
2023	2023	GEORGIA TECH RESEARCH CORPORATION	926 DALNEY ST NW	ATLANTA	GA	30332	FULTON	USA	Cancer Biology Research	002	4	6/21/2023	SUPPLEMENT FOR EXPANSION	$78,992
2023	2023	GEORGIA TECH RESEARCH CORPORATION	926 DALNEY ST NW	ATLANTA	GA	30332	FULTON	USA	Cancer Biology Research	000	4	6/15/2023	NON-COMPETING CONTINUATION	$616,381
2023	2023	GEORGIA TECH RESEARCH CORPORATION	926 DALNEY ST NW	ATLANTA	GA	30332	FULTON	USA	Cancer Biology Research	001	4	6/16/2023	SUPPLEMENT FOR EXPANSION	$79,874
														Subtotal = $775,247

Issue Date FY: 2022 ( Subtotal = $702,850 )
2022	2022	GEORGIA TECH RESEARCH CORPORATION	926 DALNEY ST NW	ATLANTA	GA	30332	FULTON	USA	Cancer Biology Research	000	3	6/2/2022	NON-COMPETING CONTINUATION	$623,860
2022	2022	GEORGIA TECH RESEARCH CORPORATION	926 DALNEY ST NW	ATLANTA	GA	30332	FULTON	USA	Cancer Biology Research	001	3	6/7/2022	SUPPLEMENT FOR EXPANSION	$78,990
														Subtotal = $702,850

Issue Date FY: 2021 ( Subtotal = $716,154 )
2021	2021	GEORGIA TECH RESEARCH CORPORATION	926 DALNEY ST NW	ATLANTA	GA	30332	FULTON	USA	Cancer Biology Research	000	2	5/21/2021	NON-COMPETING CONTINUATION	$640,183
2021	2021	GEORGIA TECH RESEARCH CORPORATION	926 DALNEY ST NW	ATLANTA	GA	30332	FULTON	USA	Cancer Biology Research	001	2	9/16/2021	SUPPLEMENT FOR EXPANSION	$75,971
														Subtotal = $716,154

Issue Date FY: 2020 ( Subtotal = $656,845 )
2020	2020	GEORGIA TECH RESEARCH CORPORATION	926 DALNEY ST NW	ATLANTA	GA	30318	FULTON	USA	Cancer Biology Research	000	1	5/29/2020	NEW	$656,845
														Subtotal = $656,845

Grand Total All Awards = $3,532,601

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Exploiting the Mechanobiology of PD-1 for Cancer Immunotherapy

Award Number: U01CA250040

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

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

PERIOD OF PERFORMANCE START DATE: 06/01/2020

PERIOD OF PERFORMANCE END DATE: 05/31/2025

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