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

Bile acids restrict functional reprogramming of myeloid-derived suppressor cells in tumor beds

Award Number: R01CA262121
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/15/2021
PERIOD OF PERFORMANCE END DATE: 08/31/2026

Group Awards By:

View Award Description

Bile acids restrict functional reprogramming of myeloid-derived suppressor cells in tumor beds - ABSTRACT The expansion of myeloid-derived suppressor cells (MDSC) in tumor-bearing hosts has emerged as a primary mechanism to limit protective anti-tumor T cell responses and a major obstacle to the success of cancer immunotherapy. It is therefore imperative to develop new effective therapeutic strategies to overcome the immune restricting effects induced by MDSC in tumors. Our recent studies demonstrated that MDSC chronically activate an integrated signaling network known as the unfolded protein responses (UPR) as a reaction to the sustained and pronounced endoplasmic reticulum (ER) stress induced by the precarious conditions of the tumor microenvironment (TME). Also, conditional deletion of the UPR-related PKR-like ER kinase (PERK) functionally reprogrammed MDSC into immunostimulatory cells that partially restore protective anti-tumor immunity in tumor beds. Importantly, our new Preliminary Results demonstrate a compensatory accumulation of highly immune- regulatory primary and secondary bile acids (BAs) in PERK-ablated MDSC in tumors. BAs are synthetized in the liver and intestine as final products of cholesterol metabolism and signal through priming of farnesoid X receptor (FXR) transcription factor, which was found increased in PERK-null MDSC and augmented MDSC suppressive activity. Based on these crucial findings, we hypothesize that the accumulation of intracellular BAs restricts the transformation of PERK-null MDSC in tumors into myeloid cells that promote sustained protective T cell immunity through activation of FXR and a subsequent induction of the compensatory UPR mediators, IRE1→Xbp1. We also propose that inhibition of PERK plus IRE1 will completely overcome MDSC-linked suppression in tumors and synergize with T cell and checkpoint immunotherapies. We propose the following Specific Aims: In Aim 1, we will determine the restrictive action of the accumulated BAs in the functional transformation of PERK-null MDSC into myeloid cells that prime sustained protective anti-tumor T cell immunity. In Aim 2, we will elucidate the mechanisms whereby BAs restrict PERKKO MDSC transformation in tumors. In Aim 3, we will test the prediction that combined inhibition of PERK and IRE1 completely overcomes MDSC- associated immunosuppression and enhances the effectiveness of cancer immunotherapy. The metabolic mediators driving the immunosuppressive functionality of MDSC in tumor beds remain poorly described. Thus, development of the Aims will have a profound impact on the field by substantiating a major metabolic signal whereby tumors restrict the functional transformation of MDSC after targeting the ER stress mediator, PERK. Also, our proposal will provide a mechanistic rationale for the development of novel therapeutic approaches to entirely reprogram immunosuppressive myelopoiesis in tumor-bearing hosts, which is likely to synergize with cancer immunotherapy and provide new biomarkers for tumor-MDSC reprogramming.


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 = $376,751 )
2025	2025	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 USF MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Cancer Biology Research	000	5	7/16/2025	NON-COMPETING CONTINUATION	$376,751
														Subtotal = $376,751

Issue Date FY: 2024 ( Subtotal = $357,915 )
2024	2024	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 USF MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Cancer Biology Research	000	4	7/25/2024	NON-COMPETING CONTINUATION	$357,915
														Subtotal = $357,915

Issue Date FY: 2023 ( Subtotal = $369,216 )
2023	2023	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Cancer Biology Research	000	3	8/17/2023	NON-COMPETING CONTINUATION	$369,216
														Subtotal = $369,216

Issue Date FY: 2022 ( Subtotal = $579,841 )
2022	2022	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Cancer Biology Research	001	2	9/7/2022	SUPPLEMENT FOR EXPANSION	$210,625
2022	2022	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Cancer Biology Research	000	2	8/30/2022	NON-COMPETING CONTINUATION	$369,216
														Subtotal = $579,841

Issue Date FY: 2021 ( Subtotal = $376,751 )
2021	2021	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Cancer Biology Research	000	1	9/6/2021	NEW	$376,751
														Subtotal = $376,751

Grand Total All Awards = $2,060,474

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Bile acids restrict functional reprogramming of myeloid-derived suppressor cells in tumor beds

Award Number: R01CA262121

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/15/2021

PERIOD OF PERFORMANCE END DATE: 08/31/2026

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer