Abstract C231: Colony-stimulating factor-1 receptor blockade reprograms malignant mesothelioma tumor microenvironments and decreases tumor growth.
Authors: Blakely Collin M. , Kolhatkar Nikita , Johansson Magnus , Hainer Cornelia M. , Wheeler Melissa , Yagui-Beltran Adam , Bueno Raphael , Sugarbaker David J. , Jahan Thierry M. , West Brian L. , Jablons David M. , Broaddus V. Courtney , Coussens Lisa M. 
Published: June 2012

Abstract
Malignant mesothelioma (MM) is a debilitating, frequently incurable cancer that exhibits a high degree of resistance to standard cytotoxic chemotherapy (CTX). Novel therapeutic approaches to treat this disease are desperately needed. In the vast majority of cases, MM is associated with prior exposure to asbestos fibers, resulting in a chronic pro-inflammatory state in pleura. As such, we hypothesized that infiltration of MM by leukocytes fosters tumorigenesis. To investigate this, we evaluated MMs resected from patients (n=16) and compared the complexity of immune cells infiltrating MM to those found in normal pleura (n=4). Using polychromatic fluorescent-activated cell sorting (FACS) on freshly resected whole tissues, we found a significant increased presence of CD11b+CD14+HLA-DR+ monocytes/macrophages in MM (37.3 ± 4.4% of total CD45+ cells) as compared to normal pleural tissue (13.8 ± 6.5% of total CD45+ cells), and a further increase in MM resected from patients treated with neoadjuvant CTX (48.8 ± 5.5% of CD45+ cells). To determine if increased presence of CD11b+CD14+HLA-DR+ leukocytes was associated with varied expression of cytokines regulating leukocyte maturation/recruitment, we examined mRNA expression of tissues/tumors. We found increased expression of Colony Stimulating Factor 1 (CSF1), and Colony-Stimulating Factor-1 Receptor (CSF-1R) mRNA, a critical cytokine-signaling axis regulating monocyte/macrophage differentiation and recruitment into tumors, in MM tumors compared to normal pleura, and even higher levels in tumors resected from patients treated with CTX. Since recent experimental data has revealed that tumor-associated macrophages (TAMs) secrete proangiogenic, prosurvival, and pro-invasive factors that foster tumor progression, we evaluated macrophage depletion in MM as a novel therapeutic strategy. We conducted studies evaluating PLX3397 (Plexxikon Inc., Berkeley, CA), a novel, orally bioavailable, small-molecule tyrosine kinase inhibitor of CSF-1R. Using a syngeneic orthotopic murine model of MM, we found that treatment of mice with PLX3397 alters the tumor immune microenvironment by decreasing TAM infiltration and increasing the proportion of CD8+ cytotoxic T lymphocytes within tumors. This reprogramming of the tumor immune microenvironment was associated with alterations in the tumor microvasculature as evidenced by a decrease in CD31+ structures, as well as a decrease in VEGFA mRNA expression. Ultimately, these changes resulted in an increase in tumor cell apoptosis (p=0.04) and a decrease in tumor burden (p=0.0008). These studies indicate that: 1) macrophages potentiate mesothelioma development, and 2) depletion of mesothelioma-associated macrophages may improve the efficacy of cytotoxic chemotherapy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C231.