Tuesday, October 7, 2025 10/7/2025

Mechanisms of immunotherapy response and resistance in pancreatic ductal adenocarcinoma

Award Number: R01CA249393
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/01/2021
PERIOD OF PERFORMANCE END DATE: 02/28/2026

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Mechanisms of immunotherapy response and resistance in pancreatic ductal adenocarcinoma - PROJECT SUMMARY Pancreatic ductal adenocarcinoma (PDA) is a lethal disease notoriously resistant to therapy including immune checkpoint blockade. Meanwhile, immunotherapy targeting the PD-1:PD-L1 pathway is inducing stunning clinical outcomes in other advanced malignancies. Despite decades of cancer immunology research, the underlying mechanisms governing immune surveillance in pancreas cancer are largely unknown. This is due, in part, to a lack of animal models that permit the detection of tumor-specific T lymphocytes during disparate clinical outcomes commonly observed in patients. We have filled this knowledge gap by creating novel animal models that permit the interrogation or the rare tumor-antigen specific T cells over time. Based on our recent discoveries, we are now uniquely poised to identify how to safely promote antigen-specific T cell-mediated destruction of pancreas cancer, and our proposal will use these results to develop a novel preclinical combination immune-based therapy to inform a clinical trial. Our compelling preliminary data support the hypothesis that immune-mediated pancreas cancer eradication requires a combination of a 1) high affinity tumor specific T cell, 2) modifying suppressive intratumoral myeloid cells, and 3) overcoming chronic inflammatory signaling mediated by TNFα. We screened a series of immunotherapies and identified that agonistic αCD40 or PD-L1 blockade has only transient antitumor activity whereas the combination leads to tumor eradication in 63% of animals. PD-L1 blockade failed to reinvigorate intratumoral T cell functions and instead changed the peripheral tumor-specific T cell repertoire and expands a unique peripheral T cell subpopulation enriched for pro-survival genes and Ikzf2. In contrast, agonistic αCD40 promotes potent, yet short-lived, cytolytic intratumoral T cells which correlates with a decrease in intratumoral myeloid cell IL-27 production. Finally, abrogating Tnfr1 expression by non-tumor/host cells overcomes tumor escape resulting in 100% of tumor eradication in αCD40+αPD-L1-treated animals. In Aim 1, we will identify the functional significance of the altered TCR repertoire and the Ikzf2+ T cell subpopulation induced following PD-L1 blockade. In Aim 2, we will test if agonistic αCD40 promotes potent cytolytic effector T cells by abrogating intratumoral myeloid cell production of IL-27 and/or CD8 T cell production of IL-10. In Aim 3, we will identify how IFNγ and TNFα signaling on non-tumor/host cells lead to disparate outcomes following combination immunotherapy of pancreas cancer and test a novel combinatorial immunotherapy that includes TNFα blockade in combination with a CD40 agonist and a PD-1 inhibitor. The studies are designed to identify a mechanistic basis for T cell dysfunction in pancreas cancer and to create a feasible clinical strategy to overcome it with the goal to create a safe and effective immune-based treatment for pancreas cancer patients.


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 = $431,993 )
2025	2025	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Cancer Biology Research	000	5	2/13/2025	NON-COMPETING CONTINUATION	$388,795
2025	2025	REGENTS OF THE UNIVERSITY OF MINNESOTA	2221 UNIVERSITY AVE SE STE 100	MINNEAPOLIS	MN	55414	HENNEPIN	USA	Cancer Biology Research	001	5	5/22/2025	NON-COMPETING CONTINUATION	$43,198
														Subtotal = $431,993

Issue Date FY: 2024 ( Subtotal = $410,395 )
2024	2024	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Cancer Biology Research	001	4	4/18/2024	NON-COMPETING CONTINUATION	$21,600
2024	2024	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Cancer Biology Research	000	4	2/14/2024	NON-COMPETING CONTINUATION	$388,795
														Subtotal = $410,395

Issue Date FY: 2023 ( Subtotal = $423,354 )
2023	2023	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Cancer Biology Research	000	3	2/28/2023	NON-COMPETING CONTINUATION	$423,354
														Subtotal = $423,354

Issue Date FY: 2022 ( Subtotal = $423,354 )
2022	2022	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Cancer Biology Research	001	2	5/19/2022	NON-COMPETING CONTINUATION	$34,563
2022	2022	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Cancer Biology Research	000	2	3/10/2022	NON-COMPETING CONTINUATION	$388,791
														Subtotal = $423,354

Issue Date FY: 2021 ( Subtotal = $431,094 )
2021	2021	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Cancer Biology Research	000	1	2/23/2021	NEW	$431,094
														Subtotal = $431,094

Grand Total All Awards = $2,120,190

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Mechanisms of immunotherapy response and resistance in pancreatic ductal adenocarcinoma

Award Number: R01CA249393

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 03/01/2021

PERIOD OF PERFORMANCE END DATE: 02/28/2026

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