Biology of extracellular vesicles and the potential of tumor-derived vesicles for subverting immunotherapy of cancer.

Abstract

Extracellular vesicles (EVs) are produced by all living cells and are present in all body fluids. EVs are heterogeneous in size, biogenesis, molecular/genetic content and functions. They constitute a part of the intercellular communication system. Among them, a subset of small EVs (sEVs) (30-150 nm) originating in the tumor cell endosomes and often referred to as "tumor cell-derived exosomes" have been of special interest. Tumors have adapted sEV they produce to promoting their own survival. Plasma of patients with cancer contains variably elevated numbers of tumor-derived sEV called "TEX," which differ from circulating sEV produced by non-malignant cells by the immunosuppressive phenotype and the molecular/genetic content. Immunosuppressive molecular profiles and abilities to signal, enter and functionally reprogram a variety of recipient cells enable TEX to exert pro-tumor effects that promote tumor resistance to immunotherapy. This review describes phenotypic and functional attributes of TEX that underline their reprogramming capabilities. It also considers mechanisms responsible for TEX pro-tumor activities and the potential significance of TEX signaling for responses of patients with cancer to immune therapies.