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

Mechanisms of JAG1-mediated immune suppression in the pancreatic cancer microenvironment

Award Number: R01CA294584
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2024
PERIOD OF PERFORMANCE END DATE: 06/30/2029

Group Awards By:

View Award Description

Mechanisms of JAG1-mediated immune suppression in the pancreatic cancer microenvironment - Pancreatic cancer (PanCan) is notorious for its resistance to therapy including immunotherapy, which is largely contributed by a suppressive tumor microenvironment. Targeting molecular pathways integral to PanCan resistance to current therapy remains an unmet need. Notch signaling regulates PanCan growth, metastasis, and the tumor microenvironment. While other studies have shown that Notch signaling in macrophage and myeloid derived suppressor cells plays an immune-suppressive role in breast cancer and lung cancer, for example, our proposal will study previously unrecognized role of JAG1 in the regulation of the metabolic fitness of conventional dendritic cells (cDCs) that underlies the poor anti-tumor responses to immunotherapy. The overarching objective of this application is to define if targeting Jagged1 (JAG1), a Notch ligand, whose expression correlates with a worse prognosis and inversely correlates with BATF3, essential for type I cDC (cDC1) development, could reverse the immunotherapy resistance in tumors with poor tumor-infiltrating cDC1 and T cells. cDC1 cells present tumor antigens to tumor-killing T cells and thus play a critical role in supporting T cell anti- tumor immunity in immunotherapy. However, dendritic cells are present in low numbers and often display functional suppression in pancreatic cancer patients. Our recent work revealed that JAG1 functions as an inhibitory Notch ligand for cDC1 development as well as cDC metabolic fitness. We also found that ablating JAG1 induced marked tumor regression and prolonged tumor-bearing mice long-term survival by increasing and reviving tumor-infiltrating DCs and Notch-activated tumor-killing T cells. We will test our central hypothesis that JAG1 promotes PanCan therapy resistance by suppressing cDC1 metabolic fitness and CD8 T cell anti-tumor response through three interrelated aims. In aim 1, we will test if anti-JAG1 blocking antibody could sensitize resistant tumors to immunotherapy. In aim 2, we will investigate the mechanism by which JAG1 impairs cDC metabolic fitness essential for anti-tumor activation. Aim 3 will focus on the mechanism of anti-tumor T cell reinvigoration mediated by JAG1 ablation/blockade. We will use a combination of the autochthonous KPC mouse model, immunophenotypically defined KPC orthotopic tumors, human PanCan organoids/myeloid cell coculture, and human PanCan specimens. We will employ cutting-edge mass cytometry to investigate the interplay between tumor cells and the surrounding immune cells and the tumor stroma. We will integrate the immunophenotyping and the spatial transcriptomics of rare immune cell populations with clinical and histopathological information to correlate molecular findings with patient outcomes. This work is innovative as we illuminate a novel function of JAG1 in the maintenance of PanCan therapy resistance and explore its potential as a novel immunomodulatory treatment for this deadly disease.


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: 2026 ( Subtotal = $1,971,221 )
2026	2026	THE METHODIST HOSPITAL RESEARCH INSTITUTE	6565 FANNIN ST STE D200	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	001	3	6/25/2026	EXTENSION WITH OR WITHOUT FUNDS	$1,971,221
2026	2025	THE METHODIST HOSPITAL RESEARCH INSTITUTE	6565 FANNIN ST STE D200	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	2	6/23/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $1,971,221

Issue Date FY: 2025 ( Subtotal = $657,074 )
2025	2025	METHODIST HOSPITAL, THE	6670 BERTNER AVE	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	2	6/9/2025	NON-COMPETING CONTINUATION	$657,074
														Subtotal = $657,074

Issue Date FY: 2024 ( Subtotal = $687,824 )
2024	2024	METHODIST HOSPITAL, THE	6670 BERTNER AVE	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	1	6/28/2024	NEW	$687,824
														Subtotal = $687,824

Grand Total All Awards = $3,316,119

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Mechanisms of JAG1-mediated immune suppression in the pancreatic cancer microenvironment

Award Number: R01CA294584

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/01/2024

PERIOD OF PERFORMANCE END DATE: 06/30/2029

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer