Growing evidence suggests that tumor-associated macrophages (TAM) are the most common immune-related stroma cells in the tumor microenvironment (TME) and the cross-talk between cancer cells and TAM ultimately results in an environment that fosters tumor growth and metastasis. However the mechanisms that drive the pro-tumor functions of TAMs are not fully understood. There has been an increasing focus on how tumor-derived extracellular vesicles (EVs) contribute to the complex intracellular communications within the TME. In ovarian cancer (OvCa), macrophages are reprogrammed toward pro-tumorigenic phenotypes, including the release of anti-inflammatory cytokines and expression of the immunosuppressive molecules such as arginase-1 and programmed death ligand-1 (PD-L1). The expression of genes involved in the inflammatory response is tightly regulated at the transcriptional and post-translational levels. To understand the mechanism driving pro-tumorigenic phenotype in macrophages, we studied the role of tumor cell-derived EVs in the cross-talk with macrophages in OvCa. We found that EVs from ovarian cancer cells contain eukaryotic translation initiation factor 4A1 (eIF4A1). eIF4A1 containing EVs from ovarian cancer cells enhanced PD-L1 expression in macrophages. However, a detailed mechanism explaining how eIF4A1-packaged EVs induce immunosuppressive phenotype in macrophages is necessary to develop novel immunotherapy strategies for advancing OvCa treatment.
This grant was made possible in part by generous donations from family and friends in loving memory of Tiffany Young.
Dr. Sonam Mittal is currently a postdoctoral researcher in the laboratory of Dr. Sunila Pradeep at the Medical College of Wisconsin, Milwaukee. Dr. Sonam Mittal earned her Ph.D. in Biotechnology from Jawaharlal Nehru University, New Delhi, India, under the mentorship of Dr. Syamala Maitreyi Rajala. Her Ph.D. research focused on understanding the role of epidermal growth factor receptor mutations in non-small cell lung cancer growth and metastasis. With a great interest in cancer biology and immunotherapy, Dr. Sonam Mittal joined Pradeep’s lab for her postdoctoral research in 2020. Her research focuses on extracellular vesicle-mediated effects in the tumor microenvironment. She discovered that extracellular vesicles isolated from high-grade serous ovarian cancer cells reprogram the tumor microenvironment by inducing functional and phenotypic alteration in tumor-associated macrophages that provide immunosuppressive and proliferative advantages to cancer cells. With the support of the Ovarian Cancer Research Alliance, the ultimate goal of her research is to identify more effective therapeutic interventions for women with high-grade serous ovarian cancer.