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

Divergent response to radio-immunotherapy in HNSCC and PDAC is mediated by regulatory T cells

Award Number: F31DE033887
ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 09/01/2025
PERIOD OF PERFORMANCE END DATE: 02/28/2028

Group Awards By:

View Award Description

Divergent response to radio-immunotherapy in HNSCC and PDAC is mediated by regulatory T cells - Abstract Head and neck squamous cell carcinoma (HNSCC) and pancreatic adenocarcinoma (PDAC) differ in many of the genetic drivers, low responsiveness to immunotherapy remains a commonality shared between both. Resistance to therapy remains an issue and while the field awaits results from numerous ongoing clinical trials, the mechanistic underpinnings that contribute to response vs. progression remain poorly understood. Our lab has shown that radiation therapy (RT) and PD1-IL2v, an immunocytokine that selectively delivers IL2 to PD-1 expressing cells via the intermediate affinity IL-2Rβγ, promotes increased infiltration, activation, and cytotoxicity of CD8 T cells and natural killer (NK) cells in preclinical orthotopic models of HNSCC and PDAC. Although the effect is substantial and results in significant tumor regression and abrogation of metastasis, the effect is transient, and tumors reoccur in the majority of mice. We therefore sought to investigate additional immunotherapies that can be added to further sustain the anti-tumor immune response induced by RT + PD1- IL2v. OX40 is a secondary costimulatory receptor which is expressed on activated T cells and provides survival signals which are critical to maintain long term immune responses. OX40 agonism has been shown to synergize well with immune checkpoint blockade (ICB), effectively boosting anti-tumor immunity in multiple tumor models. OX40 therefore represented a suitable candidate for combinatorial therapy along with PD1-IL2v and RT. Upon the addition of αOX40, we observed a striking dichotomy in the responses between preclinical models of HNSCC and PDAC. αOX40 promotes further efficacy of RT + PD1-IL2v and drives tumor eradication in HNSCC, whereas survival is significantly decreased in PDAC compared to RT + PD1-IL2v. Regulatory T cells (Tregs), have been established as critical mediators of response in both HNSCC and PDAC, and interestingly, the depletion of Tregs re-establishes to therapy. Delving deeper into this disparity, we observed that PDAC tumor microenvironment (TME) have an increased abundance of the cytokine IL-33 and is enriched with Tregs expressing the IL-33 receptor ST2, a distinctly suppressive subset which is associated with tumor progression. We therefore hypothesize that OX40 agonism drives accelerated tumor progression in PDAC by preferentially activating ST2 expressing Tregs in the PDAC TME. Aim 1 will focus on the effect that deletion of OX40 from Tregs has on therapeutic outcomes in the context of RT + PD1-IL2v + αOX40. In Aim 2, we will explore the tumor and TME intrinsic factors that can influence the dichotomous response to our combined radio-immunotherapy. We expect that this proposal will provide a mechanistic understanding of the parameters that determine response vs. progression.


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 = $46,668 )
2026	2025	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Oral Diseases and Disorders Research	001	3	8/25/2026	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$46,668
2026	2025	THE REGENTS OF THE UNIVERSITY OF COLORADO	13001 E 17TH PL STE F428	AURORA	CO	80045	ADAMS	USA	Oral Diseases and Disorders Research	000	2	8/14/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $46,668

Issue Date FY: 2025 ( Subtotal = -$10,310 )
2025	2025	THE REGENTS OF THE UNIV. OF COLORADO	13001 E 17TH PL STE F428	AURORA	CO	80045	ADAMS	USA	Oral Diseases and Disorders Research	001	2	4/8/2025	NON-COMPETING CONTINUATION	-$48,974
2025	2025	THE REGENTS OF THE UNIV. OF COLORADO	13001 E 17TH PL STE F428	AURORA	CO	80045	ADAMS	USA	Oral Diseases and Disorders Research	000	2	3/4/2025	NON-COMPETING CONTINUATION	$48,974
2025	2024	THE REGENTS OF THE UNIV. OF COLORADO	13001 E 17TH PL STE F428	AURORA	CO	80045	ADAMS	USA	Oral Diseases and Disorders Research	002	1	4/11/2025	NEW	-$10,310
														Subtotal = -$10,310

Issue Date FY: 2024 ( Subtotal = $47,694 )
2024	2024	THE REGENTS OF THE UNIVERSITY OF COLORADO	13001 E 17TH PL STE F428	AURORA	CO	80045	ADAMS	USA	Oral Diseases and Disorders Research	000	1	2/13/2024	NEW	$47,694
2024	2024	THE REGENTS OF THE UNIVERSITY OF COLORADO	13001 E 17TH PL STE F428	AURORA	CO	80045	ADAMS	USA	Oral Diseases and Disorders Research	001	1	2/13/2024	NEW	$0
														Subtotal = $47,694

Grand Total All Awards = $84,052

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Divergent response to radio-immunotherapy in HNSCC and PDAC is mediated by regulatory T cells

Award Number: F31DE033887

ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 09/01/2025

PERIOD OF PERFORMANCE END DATE: 02/28/2028

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer