Defining the Impact of STAT5 on Tumor-Associated Macrophage Function in Breast Cancer
Abstract
Despite advances in therapies, breast cancer remains the second leading cause of cancer-related deaths in women in the United States. The development of targeted therapies has been instrumental in enhancing patient survival, specifically for patients with estrogen receptor positive (ER+) and HER2-positive (HER2+) breast cancers. Significant efforts are currently underway to develop additional targeted therapies for patients with triple-negative breast cancer and for patients with ER+ and HER2+ cancers that demonstrate resistance to endocrine and HER2-targeted therapies. It is now appreciated that during tumor growth and metastasis, cancer cells adapt to different environments by interacting with non-tumor cells within the organ site, which establishes the formation of a “tumor microenvironment.” The tumor microenvironment is essentially the soil in which the tumor grows and consists of non-tumor cells and blood vessels that surround the tumor. One of the prominent non-tumor cell types within the tumor microenvironment is the macrophage, which is normally involved in the immune response to fight infections. Depending upon the factors they are exposed to, macrophages are capable of either tumor-inhibiting or tumor-promoting functions. If properly activated, macrophages can effectively kill tumor cells and engage anti-tumor immune responses, which has important implications for preventing recurrence and metastasis. Macrophages are frequently present within breast tumors and high levels of macrophage infiltration correlate with reduced patient outcome. While macrophages within the tumor microenvironment are typically associated with tumor-promoting functions, recent studies have demonstrated that macrophages within the tumor microenvironment are complex, and that there are both tumor-promoting and tumor-inhibiting macrophage subpopulations within tumors. Our studies are focused on identifying the specific mechanisms that drive anti-tumor immune function with the goal of developing novel therapeutic approaches for expanding the anti-tumor macrophage function within both primary and metastatic breast tumors. During the initial funding period, we identified a specific pathway that impacts macrophage function within the tumor microenvironment. Specifically, we found that if properly activated, a specific transcription factor known as STAT5 modulates the expression of genes within macrophages that drive anti-tumor immune responses. We have found that this pathway is particularly relevant in cancers associated with the triple-negative subtype. Studies described in this proposal will expand upon these findings using mouse models of triple-negative breast cancer to better understand the mechanisms through which STAT5 impacts macrophage function within the tumor microenvironment. Using a well-defined cohort of patient samples, we will also examine these pathways in triple-negative patient samples and correlate them with patient outcome. These studies address the overarching challenge to identify what drives breast cancer growth and determine how to stop it. Finally, we will develop a novel approach to enhance STAT5 activity within macrophages. Notably, this approach uses a specific cytokine, GM-CSF, which is currently used in various patient populations, including cancer patients, thus these studies have high potential for clinical translation. We hypothesize that STAT5 activation in macrophages will enhance anti-tumor immune responses, resulting in inhibition of tumor growth in both primary and metastatic sites. These studies will specifically address the overarching challenge to develop effective treatment regimens that impact survival. The ultimate goal of these studies is to understand how specific signaling pathways modulate immune cells in the tumor microenvironment, which will ultimately allow for the development of more effective immune modulatory therapies for breast cancer patients. Effective engagem
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010622
Entities
People
- Kathryn L Schwertfeger
Organizations
- United States Army
- University of Minnesota