Tumor-Derived Exosomes (TEX) and Their Role in Immuno-Oncology

Abstract

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.

Circulating extracellular vesicles expressing PD1 and PD-L1 predict response and mediate resistance to checkpoint inhibitors immunotherapy in metastatic melanoma

“…Increasing evidence showed that circulating EVs may counter antitumor immunity systemically since checkpoint ligands, such as PD-L1, CTLA4, and NKG2D are expressed on their surface [ 15 – 18 ]. Due to their properties, EVs are extensively investigated in melanoma [ 19 ] and increasing data indicate that they are predictive biomarker for immunotherapy efficacy [ 20 – 22 ], since they play a role in ICI resistance mechanisms [ 23 , 24 ]. Accordingly, we discovered that a significant increase of circulating uPAR + (urokinase-type Plasminogen Activator Receptor) EVs released from melanoma, CD8 + T-cells and dendritic cells correlated with unresponsiveness in a cohort of MM patients subsequently treated with nivolumab or pembrolizumab, further supporting the notion that EV-based biomarkers are powerful tool to predict innate resistance to ICI [ 25 ].…”

Diversity of Extracellular Vesicles (EV) in Plasma of Cancer Patients

“…Clearly, the use of the best capture Abs is by far the most critical aspect of TEX immune capture from plasma. In the absence of such Abs, immune capture using a mix of Abs specific for Ags highly overexpressed on cancer cells relative to nonmalignant cells and on the EVs these cells produce could be utilized for immune capture, and this approach has been successful [26]. It is possible to perform immune capture of TEX with a cocktail of Abs carefully selected for specificity to proteins overexpressed on tumor cells and weakly expressed on non-malignant cells.…”

The Role of Tumor-Derived Exosomes (TEX) in Shaping Anti-Tumor Immune Competence

“…Instead, T cells cross talking with TEX are suppressed or induced to acquire a suppressive phenotype (i.e., develop into Treg or myeloid-derived suppressor cells). Mechanistically, TEX-mediated immune suppression involves activation in recipient immune cells of numerous inhibitory pathways, leading to a loss of anti-tumor functions [ 20 ]. Suppressive activities of TEX appear to be the major element of negative regulation that prevails in the TME.…”

“…Tumor-induced immune suppression and pro-tumor activities mediated by TEX are key components of the intricate program tumor cells have developed to favor their survival and resistance to anti-cancer therapies, including therapy with ICIs. TEX represent a highly versatile version of the communication system used by normal cells that tumors have hijacked and adapted to promote tumor progression [ 20 ]. TEX circulate freely, delivering pro-tumor and anti-immune response signals to a broad variety of cells, and represent a major barrier to anti-tumor immune therapies as well as chemotherapies [ 16 ].…”