Abstract B73: Pleiotrophin drives a pro-malignant macrophage phenotype in preclinical models of breast cancer

Abstract

Tumor-associated macrophages promote progression to malignancy, metastasis, and resistance to chemotherapy in breast and pancreatic cancer. Furthermore, macrophage recruitment in tumors correlates with a worse prognosis in breast cancer patients. The phenotype of tumor associated macrophages is influenced by many factors, including the cytokine milieu within the tumor. We have identified a population of macrophages in genetic models of breast cancer that express Vascular Endothelial Growth Factor Receptor 2 (Vegfr2). Using flow cytometry and immunohistochemical analyses, we found that this population is enriched for markers associated with macrophages that promote angiogenesis, immune suppression, and metastasis. In vitro, we identified the heparin-binding peptide, pleiotrophin (PTN), as a candidate cytokine that induces Vegfr2 and anti-inflammatory cytokine expression by macrophages. Additionally, we found that PTN-stimulated macrophages can greatly increase cancer cell migration in vitro. In the MMTV-PyMT transgenic murine model of breast cancer, we observed that expression of PTN correlates with levels of Vegfr2+ macrophages and progression to malignancy. Crizotinib, an inhibitor of the pleiotrophin receptor, Anaplastic Lymphoma Kinase, reduced anti-inflammatory and Vegfr2+ macrophages in vivo. This decrease was concomitant with a significant reduction in pulmonary metastasis. This finding was corroborated by the use of 3B10, a neutralizing pleiotrophin monoclonal antibody. The potential impact of this work includes identifying a novel biomarker of promalignant macrophages, a therapeutic strategy to target them, and developing a deeper understanding of the function of macrophages in metastasis. Citation Format: Noah Sorrelle, Kristi D. Lynn, Adrian TA Dominguez, Eric Berens, Jason E. Toombs, Anton Wellstein, Rolf A. Brekken. Pleiotrophin drives a pro-malignant macrophage phenotype in preclinical models of breast cancer [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2018;6(9 Suppl):Abstract nr B73.