# Targeting the fibroblast-immune cell crosstalk to relieve immune suppression in the pancreatic cancer microenvironment

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2024 · $536,018

## Abstract

ABSTRACT
Pancreatic cancer is characterized by an extensive fibroinflammatory reaction, or tumor stroma. While immune
cells are abundant within the stroma, they are largely immune suppressive, and therefore pancreatic cancer is
largely unresponsive to immunotherapy. Genetically engineered mouse models of pancreatic cancer
recapitulate the stepwise progression of pancreatic cancer, and are ideal to study precursor lesions, such as
pancreatic intraepithelial neoplasia (PanIN). Analysis of the immune infiltrates at the PanIN stage revealed that
immune suppression is established very early on and precedes malignant progression. The mechanisms
underlying the establishment of the immune suppression in pancreatic cancer remain unknown and
understanding them is of fundamental importance to design new chemotherapy approaches for pancreatic
cancer. We previously used single cell RNA sequencing to characterize gene expression profiles in the human
pancreatic cancer immune infiltrate. We then mapped potential cell-cell interactions within the microenvironment
based on reciprocal expression of ligands and receptors. Among predicted interactions, we identified WNT
signaling activation in the T cell compartment of pancreatic cancer, driven by ligands expressed by tumor cells
and cancer associated fibroblasts (CAFs). We and others have previously associated inappropriate activation of
embryonic signaling pathways, including WNT signaling, as a characteristic of pancreatic cancer. WNT signaling
is one of the core pathways activated in pancreatic cancer. We previously showed that ablation of epithelial WNT
signaling inhibits the onset of pancreatic carcinogenesis, but the potential role of WNT in the pancreatic cancer
microenvironment and specifically in immune cells is unknown. CAFs express several ligands of the WNT family;
to ablate their expression, we inactivated PORCN (PORCUPINE), a transmembrane enzyme required for
acylation and secretion of WNT ligands, in pancreatic fibroblasts. We then transplanted pancreatic cancer cells
and observed reduced growth. To determine whether T cell activation of WNT signaling was important for this
effect, we generated mice where the transcription factors TCF7, encoding for the protein TCF1, was inactivated
in CD4+ T cells. In these animals, we observed reduced growth of transplanted tumors, alterations in the CAF
phenotype, and increased activation of anti-tumor immunity. In this proposal, we plan to build on our preliminary
data to dissect the mechanism of WNT signaling driven immune suppression in pancreatic cancer. The long term
goal is to design targeting approaches that might reverse immune suppression in this disease.

## Key facts

- **NIH application ID:** 10904995
- **Project number:** 5R01CA260752-03
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Marina Pasca Di Magliano
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $536,018
- **Award type:** 5
- **Project period:** 2022-09-01 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10904995

## Citation

> US National Institutes of Health, RePORTER application 10904995, Targeting the fibroblast-immune cell crosstalk to relieve immune suppression in the pancreatic cancer microenvironment (5R01CA260752-03). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10904995. Licensed CC0.

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