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NIH grant 1F31CA294586-01A1: Routes of tumor-specific CD4 T cell elimination of pancreatic cancer
Institute: {'code': 'CA', 'abbreviation': 'NCI', 'name': 'National Cancer Institute', 'admin_org_id': '12500008', 'admin_funding_url': ''}. PI: Eduardo Cruz. Award: $50114.
Start: 2026-09-18T00:00:00.
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.document fetched 2026-09-27 02:45