# Interrupting Cellular Crosstalk in the Immunosuppressive Microenvironment of Pancreas Cancer

> **NIH NIH U01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2020 · $527,973

## Abstract

Abstract
Immune therapy has shown great promise in the treatment of a number of malignancies, but
has not proven fruitful in fighting pancreatic ductal adenocarcinoma (PDA) using current
modalities. One possible reason for this is the unique biology of the pancreatic cancer in
establishing an immune suppressive microenvironment. We find that cross communication
between cancer associated fibroblasts (CAFs), tumor associated macrophages (TAMs) and
tumor cells is critical. Using animal models of PDA, we find that tumor cells polarize
macrophages to TAMs both by activating CAFs to produce IL6 and by producing specific
metabolites. TAMs then both suppress the immune response by arginine depletion by making
Arginase 1 and by producing EGFR ligands, primarily HBEGF, to stimulate pancreatic cancer
cells to express PDL1, an immune checkpoint ligand. We propose to use a combination of
matched humanized patient derived xenografts (PDXs), organoid culture systems made up of
cancer cells, immune cells and CAFs (ie “microtumors”) and a unique dual recombinase
genetically engineered mouse model of PDA to test the hypothesis that treatment of tumors with
inhibitors of STAT3, HBEGF, ARG1 or MEK will effectively synergize with PD1 inhibition,
overcoming the powerful immune suppression created by the pancreatic cancer
microenvironment.

## Key facts

- **NIH application ID:** 10242453
- **Project number:** 4U01CA224145-02
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Howard C. Crawford
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $527,973
- **Award type:** 4N
- **Project period:** 2017-09-30 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10242453

## Citation

> US National Institutes of Health, RePORTER application 10242453, Interrupting Cellular Crosstalk in the Immunosuppressive Microenvironment of Pancreas Cancer (4U01CA224145-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10242453. Licensed CC0.

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