Daniel C Rabe

Harvard Medical School, USA

Title: Tumor extracellular vesicles regulate macrophage driven me-tastasis through CCL5

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Biography

Dr. Daniel Rabe is a postdoctoral fellow in the lab of Dr. Shannon Stott at Massachusetts General Hospital. He seeks to elucidate crosstalk between tumor and immune cells through extracellular vesicles (EVs) to better understand how some tumors become metastatic and resistant to therapy. Dr. Rabe utilized novel microfluidics to capture and characterize EVs from patient blood to better understand their impact and utility as biomarkers in cancer. By comparing EV signatures in patients to the tumor-immune infiltrate, Dr. Rabe seeks to better understand the role EVs play in the process of metastasis and therapy resistance. Additionally, he seeks to understand how signaling pathways in the tumor alter EV biology, and thereby alter the biology of the immune infiltrate.

Abstract

To determine how tumors alter macrophages recruited to triple-negative breast cancer (TNBC) tumors by CCL5, we utilized bone marrow derived macrophage (BMDMs) treated with either: recombinant CCL5 protein; tumor cell conditioned media; or enriched tumor extracellular vesicles (EVs). To determine the impact of these treated macrophages on tumor cell invasion, we pretreated tumor cells with macrophage conditioned media prior to performing the invasion assay. We found that tumor EVs alone are capable of programming naïve macrophages toward a pro-metastatic, “M2-like” phenotype, while CCL5 protein did not alter macrophage biology. We then assaying secreted cytokines from these TEMs to determine how they may alter tumor cells. Analysis of the tumor EV-educated macrophages (TEMs) showed secretion of a variety of factors including CXCL1, CTLA-4, IFNG, OPN, HGF, TGFB, and CCL19 capable of remodeling the tumor stroma and immune infiltrate as well as driving tumor cell invasion. We found that alterations of tumor CCL5 expression regulates both biogenesis/secretion of EVs and their ability to alter macrophage education toward a pro-metastatic phenotype. Injection of tumor cells with metastatic tumor derived EV-educated macrophages into mice increased tumor metastasis to the lung as well as recruitment of T-regulatory cells. These results demonstrate that tumor-derived EVs are key mediators of macrophage education and likely play a more complex role in modulating tumor therapeutic response by regulating the tumor immune infiltrate.