A. Macrophage Activation in Autoimmunity
The autoimmune disease systemic sclerosis (SSC) is characterized by inflammation, vascular dysfunction, and fibrosis. While most studies have focused on fibroblasts as mediators of tissue damage in this disease, the role of inappropriate innate immune activation has only recently been recognized. We hypothesize that activated macrophages mediate fibrotic activation in patients with SSc. The goal of our work is to provide the basis for rational therapeutic targeting in these patients, for whom current treatment options are very limited. Our data have shown macrophages are likely drivers of fibrosis in SSc and have key interactions with fibroblasts and other immune cells to create a pro-fibrotic microenvironment in target tissues. Our current studies are focused on identifying the signaling pathways that regulate SSc macrophage activation, the role that activated macrophages play in enhancing fibrosis in SSc, and immune-based mechanisms to inhibit pro-fibrotic activation.
B. Redirection of Macrophage Activation in Breast Cancer
Treatment options for patients with triple negative breast cancer (TNBC) are limited by a lack of clearly defined therapeutic targets. Macrophages can constitute up to 50% of the total cells in the tumor microenvironment and contribute to the pathogenesis of breast cancer. However, because macrophages are plastic, activation of these cells can potentially be changed to attack instead of support tumor cell growth. In recent studies, we have shown that a drug currently undergoing Phase II/III clinical trial testing, the synthetic triterpenoid CDDO-Me, alters activation of macrophages in breast tumors, resulting in their ability to stimulate instead of suppress the immune response. Successfully targeting cells that are responsible for protecting and enhancing growing tumors could tip the balance, and expose unreachable and protected vulnerabilities of the tumor in terms of nutrient supply and oxygenation, therapeutic resistance, and especially, to the awakening of the immune system. Current studies are focused on characterizing the ability of CDDO-Me to reprogram tumor-associated macrophage (TAM) activation in other types of cancer, including melanoma, determining the efficacy of this drug in inhibiting metastatic tumor growth, and assessing the utility of CDDO-Me to enhance the efficacy of standard chemotherapy and potentially other immunotherapies.