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Routes of tumor-specific CD4 T cell elimination of pancreatic cancer

Award Number: F31CA294586
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 09/18/2026
PERIOD OF PERFORMANCE END DATE: 09/17/2028

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Routes of tumor-specific CD4 T cell elimination of pancreatic cancer - PROJECT ABSTRACT Pancreatic ductal adenocarcinoma (PDA) is the fourth leading cause of cancer related deaths in the United States and has a dismal 5-year survival rate of 12%. Antibody-based immunotherapy shows benefit in a small subset of PDA patients, suggesting that these therapies could be improved to benefit a larger fraction of the patient population. Increasingly recognized as a critical component of antitumor immunity, conventional antigen-experienced CD4 T cells are associated with better prognosis and immunotherapy efficacy. However, the effects of immunotherapy on CD4 T cell fate, antigen-recognition, antitumor function, and immune interactions are poorly understood. As such, this grant seeks to deepen our understanding of tumor-specific CD4 T cell dynamics following immunotherapy with the goal of identifying novel therapeutic opportunities to improve the efficacy of immunotherapy against PDA. Using a novel peptide:MHC II tetramer, my preliminary data indicates tumor infiltrating antigen-specific CD4 T cell numbers, particularly the T helper 1 (Th1) subset, significantly decrease at late tumor growth stages. Treating mice with agCD40 monotherapy or in combination with αPD-L1 restores intratumoral Th1 frequency and decreases immunosuppressive tumor-specific regulatory CD4 T cells (Treg). One consideration is that these preliminary findings are from a CD4 T cell specific to a subdominant epitope. Therefore, for my first Aim, I propose leveraging an anti-PDA CD4 TCR transgenic mouse strain to investigate CD4 T cell phenotype, function, and antigen-recognition following immunotherapy. I generated a Trac-inserted TCR exchange transgenic mouse strain (TrexCB440) where CD4 T cells target a likely immunodominant model neoepitope (CB440) engineered in our KPC PDA cell lines. I will characterize thymic and peripheral CD4 T cells development in TrexCB440 mice to confirm normal lymphocyte development. TrexCB440 will enable the study of tumor-specific CD4 T cell fate, persistence, and polarization in PDA. This strain will be used to determine whether macrophage MHC-II is essential for shaping the CD4 T cell phenotype induced by immunotherapy. Our recently published results suggest CD4 T cell recognition of tumor antigen through tumor-associated macrophages (TAMs) MHC-II drives the antitumor effects of TAMs. Thus, in my second Aim, I will identify the macrophage-CD4 cell-to-cell signals that drive antitumor activity. I will perform physically interacting cell sequencing (PIC-seq) of intratumoral CD4 T cell-TAM doublets to identify CD4 T cell immunotherapy-induced signals that result in macrophage activated phenotype. Finally, I will conduct an in vivo CRISPR gene knockout assay to define specific mechanisms through which immunotherapy induces CD4 T cell tumor control. Successful completion of the proposed research strategy will reveal novel routes by which antigen-specific CD4 T cells contribute to pancreatic tumor control and the longevity of the immunotherapy response.


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 = $50,114 )
2026	2026	REGENTS OF THE UNIVERSITY OF MINNESOTA	2221 UNIVERSITY AVE SE STE 100	MINNEAPOLIS	MN	55414	HENNEPIN	USA	Cancer Research Manpower	000	1	9/8/2026	NEW	$50,114
2026	2026	REGENTS OF THE UNIVERSITY OF MINNESOTA	2221 UNIVERSITY AVE SE STE 100	MINNEAPOLIS	MN	55414	HENNEPIN	USA	Cancer Research Manpower	001	1	9/8/2026	NEW	$0
														Subtotal = $50,114

Grand Total All Awards = $50,114

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Routes of tumor-specific CD4 T cell elimination of pancreatic cancer

Award Number: F31CA294586

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 09/18/2026

PERIOD OF PERFORMANCE END DATE: 09/17/2028

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