Extracellular vesicles (EVs) play a key role in health and disease, including
cancer.
Tumors produce a mix of EVs differing in size, cellular origin, biogenesis and molecular content. Small EVs (sEV) or exosomes are a subset of 30-150 nm (virus-size) vesicles originating from the multivesicular bodies (MVBs) and carrying a cargo that in its content and topography approximates that of a parent cell.
Tumor-derived exosomes (TEX) present in all body fluids of
cancer patients, are considered promising candidates for a liquid
tumor biopsy. TEX also mediate immunoregulatory activities: they maintain a crosstalk between the
tumor and various non-malignant cells, including immunocytes. Effects that EVs exert on immune cells may be immunosuppressive or immunostimulatory. Here, we review the available data for TEX interactions with immunocytes, focusing on strategies that allow isolation from plasma and separation of TEX from sEV produced by non-malignant cells. Immune effects mediated by either of the subsets can now be distinguished and measured. The approach has allowed for the comparison of molecular and functional profiles of the two sEV fractions in plasma of
cancer patients. While TEX carried an excess of immunosuppressive
proteins and inhibited immune cell functions in vitro and in vivo, the sEV derived from non-malignant cells, including CD3(+)T cells, were variably enriched in immunostimulatory
proteins and could promote functions of immunocytes. Thus, sEV in plasma of
cancer patients are heterogenous, representing a complex molecular network which is not evident in healthy donors' plasma. Importantly, TEX appear to be able to reprogram functions of non-malignant CD3(+)T cells inducing them to produce CD3(+)sEV enriched in immunosuppressive
proteins. Ratios of stimulatory/inhibitory
proteins carried by TEX and by CD3(+)sEV derived from reprogrammed non-malignant cells vary broadly in patients and appear to negatively correlate with
disease progression. Simultaneous capture from plasma and functional/molecular profiling of TEX and the CD3(+)sEV fractions allows for defining their role as
cancer biomarkers and as monitors of
cancer patients' immune competence, respectively.