Thursday, November 21, 2024 11/21/2024

The effects of PD-1 on tumor-mediated “emergency” myelopoiesis and fate commitment of myeloid cells: Implications for anti-tumor immunity

Award Number: R01CA238263
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

Group Awards By:

View Award Abstract

PD-1 blocking agents have achieved significant success as anti-cancer therapeutics. The mechanism(s) of how PD-1 compromises anti-tumor function remain poorly understood. We generated an antibody that recognizes PD-1pY248 that is required for PD-1 inhibitory signaling. In three mouse tumor models, we identified PD-1 expression and phosphorylation in CD4+ and CD8+ T cells of the tumor microenvironment (TME) but more prominently in myeloid cells. These findings prompted us to examine the role of PD-1 in myeloid cell differentiation and function in cancer immunity. The rapid change in hematopoietic cell output that occurs in response to immunologic stress is known as “emergency” myelopoiesis”. During continuous low-level stimulation mediated by cancer-derived factors, common myeloid progenitors (CMP) and granulocyte/macrophage progenitors (GMP), undergo modest but continuous expansion with hindered differentiation leading to the output of immature myeloid-derived suppressor cells (MDSC). We analyzed the myeloid compartment of tumor-bearing mice and determined that myeloid cells that expand during cancer-driven emergency myelopoiesis express PD- 1 and PD-L1. Using PD-1 KO mice or WT mice treated with PD-1 blocking antibody we determined that PD-1 deletion or blockade prevented the accumulation of immature myeloid progenitor cells and stimulated differentiation and output of Ly6Chi effector monocytes, macrophages and dendritic cells (DC). To determine whether these outcomes were mediated by a myeloid-intrinsic impact of PD-1 ablation or by the effects of PD- 1neg T cells on myeloid cells, we generated mice with conditional targeting of the Pdcd1 gene (PD-1f/f) and selectively eliminated PD-1 in myeloid cells or T cells. Compared to T cell-specific, myeloid cell-specific PD-1 ablation more effectively decreased tumor growth. Cancer-driven emergency myelopoiesis was differentially affected. Both myeloid-specific and T cell-specific PD-1 ablation resulted in expansion and accumulation of CMP but only myeloid-specific PD-1 ablation prevented the accumulation of GMP and switched the myeloid cell fate from MDSCs to differentiated effector monocytes, macrophages, DC. Our findings reveal a previously unidentified role of the PD-1: PD-L1 pathway and support the novel hypothesis that switch of myeloid cell fate commitment might be a key mechanism by which PD-1 blockade mediates its anti-tumor function. To investigate this, we will pursue the following specific aims to determine: 1. How PD-1 signaling mediates lineage fate determination of myeloid progenitor cells in response to emergency myelopoiesis. 2. How PD-1 targeting impacts the metabolic and epigenetic program of myeloid cells. 3. How PD-1 affects anti-tumor immunity by regulating the crosstalk between innate and tumor- associated T cells.


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 = $623,127 )
2024	2024	BETH ISRAEL DEACONESS MEDICAL CENTER, INC.	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cancer Biology Research	001	5	4/17/2024	NON-COMPETING CONTINUATION	$30,168
2024	2024	BETH ISRAEL DEACONESS MEDICAL CENTER, INC	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cancer Biology Research	000	5	1/24/2024	NON-COMPETING CONTINUATION	$542,959
2024	2024	BETH ISRAEL DEACONESS MEDICAL CENTER, INC.	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cancer Biology Research	002	5	9/6/2024	NON-COMPETING CONTINUATION	$50,000
														Subtotal = $623,127

Issue Date FY: 2023 ( Subtotal = $591,222 )
2023	2023	BETH ISRAEL DEACONESS MEDICAL CENTER, INC	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cancer Biology Research	000	4	1/31/2023	NON-COMPETING CONTINUATION	$591,222
														Subtotal = $591,222

Issue Date FY: 2022 ( Subtotal = $591,222 )
2022	2022	BETH ISRAEL DEACONESS MEDICAL CENTER, INC	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cancer Biology Research	000	3	1/5/2022	NON-COMPETING CONTINUATION	$542,959
2022	2022	BETH ISRAEL DEACONESS MEDICAL CENTER, INC	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cancer Biology Research	001	3	4/25/2022	NON-COMPETING CONTINUATION	$48,263
														Subtotal = $591,222

Issue Date FY: 2021 ( Subtotal = $631,075 )
2021	2021	BETH ISRAEL DEACONESS MEDICAL CENTER, INC	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cancer Biology Research	000	2	1/18/2021	NON-COMPETING CONTINUATION	$631,075
														Subtotal = $631,075

Issue Date FY: 2020 ( Subtotal = $642,962 )
2020	2020	BETH ISRAEL DEACONESS MEDICAL CENTER, INC	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cancer Biology Research	000	1	2/10/2020	NEW	$642,962
														Subtotal = $642,962

Grand Total All Awards = $3,079,608

Top

All Categories

About

Search

Reports

Data Submission

Award Information

The effects of PD-1 on tumor-mediated “emergency” myelopoiesis and fate commitment of myeloid cells: Implications for anti-tumor immunity

Award Number: R01CA238263

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer