Regulation of tumor associated macrophage function by STAT5 in breast cancer

University Of Minnesota, Minneapolis MN

Investigators

Abstract

PROJECT SUMMARY Breast cancer growth and progression require complex interactions between tumor cells and their surrounding environment. Increased numbers of infiltrating inflammatory cells, in particular macrophages, correlate with poor patient prognosis in breast cancer. Our studies have focused on identifying key signaling pathways within macrophages that drive their functions within the tumor microenvironment, including those that drive anti-tumor macrophage phenotypes. Specifically, we have found that treatment of macrophages with the cytokine granulocyte macrophage colony-stimulating factor (GM-CSF) drives an immunostimulatory expression profile in macrophages that is dependent upon signal transducer and activator of transcription 5 (STAT5). Furthermore, using conditional genetic knock-out approaches, we have found that loss of STAT5 signaling in macrophages leads to enhanced mammary tumor progression. This proposal focuses on further understanding the impact of STAT5 signaling in tumor associated macrophages and determining whether modulating STAT5 in macrophages impacts breast cancer growth and progression. Based on our preliminary results, we hypothesize that loss of STAT5 in macrophages promotes an immunosuppressive environment that enhances mammary tumor growth and metastasis and that restoration of STAT5 activity in macrophages will enhance anti-tumor immune responses, leading to decreased tumor growth and metastasis. Studies proposed in Specific Aim 1 will use genetic mouse models to define the effects of myeloid STAT5 deletion on mammary tumor growth and metastasis and determine the requirement for GM-CSF for STAT5 activation in tumor associated macrophages. Studies proposed in Specific Aim 2 will define the mechanisms through which modulation of STAT5 in myeloid cells impacts tumor progression by identifying direct STAT5 target genes in macrophages and assessing the roles of STAT5-regulated chemokines to modulation of the immune environment. Studies in Specific Aim 3 will develop new antibody-based approaches to determine the impact of restoring STAT5 function in macrophages on tumor growth and metastasis and use multiplex imaging to define the cellular neighborhoods associated with STAT5-activated macrophages in human breast cancer samples. The focus of these studies is to examine the impact of modulating the STAT5 pathway selectively in macrophages with a goal of enhancing anti-tumor immune responses. Obtaining a better understanding of the mechanisms through which macrophages impact tumor progression and respond to cancer therapies will ultimately lead to the development of approaches that exploit their potential anti-tumorigenic properties for therapeutic purposes.