Official websites use .gov

A .gov website belongs to an official government organization in the United States.

Secure .gov websites use HTTPS

A lock ( 🔒 ) or https:// means you've safely connected to the .gov website. Share sensitive information only on official, secure websites.

Need Help

PD-L1 interacts with CD80 and PD-1 to regulate GVHD and GVL activity

Award Number: R01CA228465
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/01/2018
PERIOD OF PERFORMANCE END DATE: 02/28/2023

Group Awards By:

View Award Description

PD-L1 interacts with CD80 and PD-1 to regulate GVHD and GVL activity - Allogeneic hematopoietic cell transplantation (HCT) is a curative therapy for relapsed hematological malignances (i.e. leukemia) due to graft-versus-leukemia (GVL) activity mediated by alloreactive T cells. However, alloreactive T cells also mediate graft-versus-host disease (GVHD), which remains the major obstacle for wide-spread application of allogeneic HCT. The long-term goal of our study is to develop novel regimens that prevent GVHD while preserving GVL activity. PD-L1 interacts with CD80 and PD-1. Although PD-L1/PD-1 regulation of immune responses plays an important role in animal models and humans, the role of PD-L1/CD80 remains largely unknown. Our recent publication in JCI has shed light on the importance of PD- L1/CD80 interactions. Our studies indicate that the outcome of PD-L1-mediated signaling in CD8+ T cells depends on the presence or absence of CD4+ T cells, the nature of the interacting receptors (i.e. CD80 versus PD-1) expressed by CD8+ T cells and the tissue environment (i.e. lymphoid versus parenchymal tissues) in which the signaling occurs. We observed that, in the absence of donor CD4+ T cells, CD8+ T-T interactions via PD-L1/CD80 augmented naïve/activating CD8+ T proliferation and survival in lymphoid tissues, leading to strong GVL activity. In contrast, host-tissue PD-L1 interactions with PD-1 and CD80 on CD8+ T cells in GVHD target tissues induced their proliferation and apoptosis, leading to prevention of GVHD. Donor CD4+ T cells helped CD8+ T cells via IL-2 become resistant against tissue PD-L1-mediated tolerance. Agonistic PD-L1-Ig binding to both CD80 and PD-1 augmented activated T cell proliferation and apoptosis. Conflicting results have been reported regarding the effects of glycolysis and oxidative phosphorylation (OXPHOS) in alloreactive T cells during the pathogenesis of acute GVHD. In kinetic studies, we observed that expression of CD80 and PD- 1 was associated with shift from glycolysis to OXPHOS. Therefore, we hypothesize that 1) PD-L1/CD80 and PD-L1/PD-1 interactions reciprocally regulate T cell glycolysis and OXPHOS, and the outcome depends on the tissue environment, due to differential T cell expression of CD80, PD-1, and PD-L1; 2) Reduction of serum IL-2 will increase the sensitivity of T cells towards tissue PD-L1-mediated or agonistic PD-L1- Ig-mediated tolerance in association with metabolic profile changes. The proposed studies will dissect the mechanisms by which PD-L1/CD80 interactions regulate glycolysis and OXPHOS in naïve/activating and activated T cells in lymphoid and GVHD target tissues (Aim 1). We will also design a regimen of sequentially administered anti-IL-2 and agonistic PD-L1-Ig to prevent GVHD and preserve strong GVL activity (Aim 2). These studies will reveal novel insights into T cell biology and GVHD pathogenesis and could lead to development of novel regimens that prevent GVHD while preserving GVL activity in humans. 1


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 = $0 )
2024	2022	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Biology Research	000	5	12/6/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $388,013 )
2022	2022	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Biology Research	001	5	5/19/2022	NON-COMPETING CONTINUATION	$31,675
2022	2022	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Biology Research	000	5	2/28/2022	NON-COMPETING CONTINUATION	$356,338
														Subtotal = $388,013

Issue Date FY: 2021 ( Subtotal = $395,932 )
2021	2021	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Biology Research	000	4	1/27/2021	NON-COMPETING CONTINUATION	$395,932
														Subtotal = $395,932

Issue Date FY: 2020 ( Subtotal = $395,946 )
2020	2020	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Biology Research	000	3	2/5/2020	NON-COMPETING CONTINUATION	$395,946
														Subtotal = $395,946

Issue Date FY: 2019 ( Subtotal = $392,146 )
2019	2019	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Biology Research	000	2	1/30/2019	NON-COMPETING CONTINUATION	$392,146
														Subtotal = $392,146

Issue Date FY: 2018 ( Subtotal = $404,275 )
2018	2018	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Biology Research	000	1	2/6/2018	NEW	$404,275
														Subtotal = $404,275

Grand Total All Awards = $1,976,312

Top

All Categories

About

Search

Reports

Data Submission

Award Information

PD-L1 interacts with CD80 and PD-1 to regulate GVHD and GVL activity

Award Number: R01CA228465

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 03/01/2018

PERIOD OF PERFORMANCE END DATE: 02/28/2023

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer