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.

Keywords: Cytokine; Immunocompromised; Immunosuppression; Immunotherapy; Tumor microenvironment - TME.

Figure 1. Biogenesis of tumor-derived exosomes. The exosome vesiculation process consists of the initial endocytosis of surface-associated molecules, their uptake by endosomes, reverse vesicle formation in late endosomes and fusion of endosomes into a multivesicular body (MVB). When the MVB fuses with the tumor cell membrane, exosomes are released into the extracellular space. They are heterogeneous in size approximating that of viruses (see the TEM image in upper right) and differ from various larger vesicles in the molecular content as well as the cellular origin. The small EV may also be formed by “budding” of the cell membrane like microvesicles. The latter originate from the cytosol by “budding” of the cell membrane. The vesiculation process is ATP-dependent and occurs in live cells. EV, extracellular vesicle; MVB, multivesicular body.

Figure 2. Exosomes from plasma of AML patients interfere with functions of NK92 cells. NK-92 cells were coincubated with exosomes isolated from pre-therapy AML plasma for 24 hours. (A) Flow cytometry of NK-92 cells illustrates downregulation of NKG2D protein. (B) Confocal microscopy illustrates the presence of GFP-labeled exosomes in NK-92 cells and downregulation of red-labeled NKG2D protein from the NK-92 cell surface. (C) Quantitation of the NKG2D downregulation in NK-92 cells. (D) A loss of NK-92 cytotoxicity. Reproduced from Hong et al.