# Modulating innate immune cells in the tumor microenvironment of pancreas cancer to enhance anti-tumor immunity

> **NIH NIH R01** · UNIVERSITY OF ROCHESTER · 2020 · $118,067

## Abstract

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy and the fourth leading cause of
cancer deaths in the United States. Surgical resection is the only known curative treatment for pancreatic
cancer. However, only 15-20% of patients present with operable disease; all others have locally advanced or
metastatic disease. Additionally, recurrence post-surgery is frequently observed, most often in the liver. We
and others have shown that tumor-initiated myeloid cell recruitment from the bone marrow to the tumor site
results in promotion of tumor growth and dissemination, as well as suppression of anti-tumor immune
responses. We now have data showing inflammatory monocyte (IM) and macrophage prevalence in the blood
and tumor, respectively, is predictive of survival. Our studies show that blockade of bone-marrow mobilization
or peripheral depletion of IM can slow tumor growth and prolong survival in murine pancreas cancer models.
Thus, our central hypothesis is that selective targeting of key regulators involved in the mobilization
and trafficking of IM holds significant promise for the treatment of pancreas cancer. The CCL2/CCR2
chemokine/receptor pathway appears critical for IM mobilization and recruitment to the tumor. Recruitment of
IM to the tumor and tumor growth is significantly reduced in mice lacking CCR2 as well as in mice treated with
an orally active CCR2 antagonist. Based on these compelling data we initiated a phase I clinical trial in patients
with locally-advanced, unresectable pancreas cancer. In Aim 1 we propose to determine if targeting CCR2
signaling through the CCR2 antagonist enhances the efficacy of chemotherapy in patients with locally-
advanced, unresectable pancreas cancer. We will explore whether CCR2 blockade reduces recruitment and
function of myeloid cells in the bone marrow, periphery and tumor; whether the immune suppressor/effector
ratio is altered in the tumor microenvironment, and whether any of these changes correlate with survival. In
addition to the clinical trial we propose several pre-clinical studies in an orthotopic mouse model of pancreatic
cancer to elucidate the mechanism and determine the optimal clinical setting for targeting CCR2/CCL2 in
pancreatic cancer. In Aim 2 we will determine if CCR2/CCL2 inhibition blocks mobilization of IM from the bone
marrow to the primary tumor site in an orthotopic murine model of pancreas cancer. Using flow cytometry,
immune cell depletion and gene expression analysis, we will determine which immune cell subset(s) is
responsible for the antitumor effect of CCR2 inhibition. To define the role of IM in initiation and propagation of
metastasis we will determine in Aim 3 if CCR2/CCL2 inhibition decreases tumor growth and distant spread in
an orthotopic, metastatic model of pancreas cancer. Finally, optimal integration of CCR2 blockade with
chemotherapy will be assessed in Aim 4 to allow for the rational design of combination therapy in subsequent
cli...

## Key facts

- **NIH application ID:** 10044714
- **Project number:** 3R01CA168863-07S1
- **Recipient organization:** UNIVERSITY OF ROCHESTER
- **Principal Investigator:** DAVID C LINEHAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $118,067
- **Award type:** 3
- **Project period:** 2013-07-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10044714

## Citation

> US National Institutes of Health, RePORTER application 10044714, Modulating innate immune cells in the tumor microenvironment of pancreas cancer to enhance anti-tumor immunity (3R01CA168863-07S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10044714. Licensed CC0.

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