Friday, January 16, 2026 1/16/2026

Tackling Treg mediated resistance to radiation and anti-PDL1 in HNSCCs

Award Number: R01DE028529
ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2019
PERIOD OF PERFORMANCE END DATE: 10/01/2024

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Tackling Treg mediated resistance to radiation and anti-PDL1 in HNSCCs - ABSTRACT We have shown that elective nodal irradiation (ENI) blunts systemic immunity in preclinical models of head and neck cancer (HNC), but without it, the risk of regional recurrence in the lymph nodes (LN) is high. Data from clinical trials showed that omission of ENI is feasible, but nodal progression or recurrence does vary by the choice of immunotherapy (IO) that is combined with the radiation (RT). Our previous trial showed that combination aPDL1 (Durvalumab) with tumor-only RT resulted in exceptional high pathological and clinical response rates and no nodal recurrences. However, in two other separate trials, when either another a- PDL1(Atezolizumab) or a-CTLA4 was added to Durvalumab-RT, it resulted in high rates of nodal recurrence leading to trial closures. This suggests that target cell activation or inhibition varies by the type of IO or combination IO used in the context of RT and dictates nodal outcome. Our preliminary data show that trial patient progressive nodes contained a high percentage of Tregs and, preclinically, genetic knockout of PD1 on Tregs increases their activation, which we have previously shown to be driven by STAT3. We demonstrate that nodal metastasis can be prevented by early depletion of Tregs prior to tumor implantation. This is accompanied by enhanced morphological maturation of high endothelial venules (HEVs), specialized postcapillary venules whose function within DLNs has been correlated with immune trafficking and activation. Localized within perivascular niches, and surrounded by Tregs and cancer cells, these HEVs, which express LTBR, are decreased in numbers and maturation on nodal recurrence, a phenomenon that is reversed by LTBR agonists. We also show that ST2 Tregs, a specific Tregs subset, are upregulated with RT and that genetic knockout of ST2 on Tregs results in marked tumor regression. Recombinant administration of IL33 (ST2's ligand), on the other hand, combined with RT and Treg depletion, leads to high rates of eradication of nodal recurrence. We hypothesize that activation of PD1 expressing Tregs in the RT-IO setting contributes to cancer immune evasion directly via STAT3 pathway activation, indirectly through LTA1B2-LTBR Treg-HEV interaction, thereby limiting the Teff infiltration into the nodal environment, and through the ST2-IL33 Treg-stromal interaction, abrogating Teff cells' expansion potential. In Aim1, we will examine the mechanistic impact of immune check point inhibition on Tregs; in Aim2, we will test how Treg-HEV interaction facilitates a tumor- promoting environment within the LN, leading to immunosuppression and cancer cell immune evasion; and in Aim 3, we will determine how ST2 expressing Tregs modulate tumor immune microenvironment in nodal progression. These will be tested using genetically engineered mouse models, multicompartmental mass cytometry, scRNA seq, metabolomic and proteomic analysis, and multispectral immunofluorescence preclinically and in clinical trial specimens from those with and without nodal failure. These studies will collectively elucidate mechanisms of nodal progression with profound impact for therapeutic discovery.


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 = $0 )
2026	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	6	12/3/2025	COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $499,311 )
2025	2025	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Oral Diseases and Disorders Research	003	7	8/4/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$499,311
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	6	8/4/2025	COMPETING CONTINUATION	$0
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	001	6	3/24/2025	COMPETING CONTINUATION	$16,137
2025	2023	THE REGENTS OF THE UNIV. OF COLORADO	13001 E 17TH PL STE F428	AURORA	CO	80045	ADAMS	USA	Oral Diseases and Disorders Research	000	5	3/24/2025	NON-COMPETING CONTINUATION	-$16,137
														Subtotal = $499,311

Issue Date FY: 2024 ( Subtotal = $495,520 )
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	002	6	7/17/2024	COMPETING CONTINUATION	$0
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	6	7/16/2024	COMPETING CONTINUATION	$495,520
2024	2023	THE REGENTS OF THE UNIVERSITY OF COLORADO	13001 E 17TH PL STE F428	AURORA	CO	80045	ADAMS	USA	Oral Diseases and Disorders Research	000	5	7/9/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $495,520

Issue Date FY: 2023 ( Subtotal = $439,092 )
2023	2023	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Oral Diseases and Disorders Research	000	5	3/7/2023	NON-COMPETING CONTINUATION	$439,092
														Subtotal = $439,092

Issue Date FY: 2022 ( Subtotal = $434,700 )
2022	2022	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Oral Diseases and Disorders Research	001	4	4/21/2022	NON-COMPETING CONTINUATION	$39,520
2022	2022	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Oral Diseases and Disorders Research	000	4	3/11/2022	NON-COMPETING CONTINUATION	$395,180
														Subtotal = $434,700

Issue Date FY: 2021 ( Subtotal = $439,092 )
2021	2021	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Oral Diseases and Disorders Research	000	3	3/18/2021	NON-COMPETING CONTINUATION	$439,092
														Subtotal = $439,092

Issue Date FY: 2020 ( Subtotal = $439,092 )
2020	2020	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Oral Diseases and Disorders Research	000	2	2/13/2020	NON-COMPETING CONTINUATION	$439,092
														Subtotal = $439,092

Issue Date FY: 2019 ( Subtotal = $439,092 )
2019	2019	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Oral Diseases and Disorders Research	001	1	5/16/2019	NEW	$0
2019	2019	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Oral Diseases and Disorders Research	000	1	3/21/2019	NEW	$439,092
														Subtotal = $439,092

Grand Total All Awards = $3,185,899

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Tackling Treg mediated resistance to radiation and anti-PDL1 in HNSCCs

Award Number: R01DE028529

ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/01/2019

PERIOD OF PERFORMANCE END DATE: 10/01/2024

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