Abstract
Plasma-derived exosomes of head and neck squamous cell carcinoma (HNSCC) patients carry inhibitory factors mediating immune suppression. Separation of tumor-derived exosomes (TEX) and non-TEX may assist in a better understanding of their respective parental cells. Here, we evaluate the impact of TEX or hematopoietic-derived exosomes on immune suppression. We evaluated apoptosis in CD8+ T cells, conversion of CD4+ T cells to regulatory T cells (Treg), and adenosine production by TEX, non-TEX, or total exosomes. Exosome protein cargo was significantly higher in total and CD45(−) exosomes from high stage compared to low stage patients. Furthermore, total and CD45(−) exosomes of high stage patients induced more apoptosis in CD8+ T cells than their low stage counterparts. CD69 suppression, a marker of reduced CD8+ T cell activation, was only mediated by CD45(−) exosomes. All fractions induced Treg differentiation, defined by CD39 expression, but only CD45(−) exosomes showed a stage-dependent conversion. CD45(−) exosomes produced higher adenosine concentrations than CD45(+) exosomes, concluding that adenosine production measured in total exosomes mainly derives from TEX. The presented results show significant induction of immune suppression by TEX in HNSCC. This immunosuppressive effect supports the potential role of exosomes as liquid biomarkers for disease stage and level of immune suppression.
Highlights
Head and neck squamous cell carcinomas (HNSCC) are highly aggressive and immunosuppressive malignancies [1,2,3]
Among other mechanisms contributing to immune suppression in the tumor microenvironment (TME) of head and neck squamous cell carcinoma (HNSCC), extracellular vesicles (EVs) such as exosomes have been identified as carriers and producers of immunosuppressive molecules
Plasma samples were pre-cleared by centrifugation at 2000 g and 100,000 g followed by ultrafiltration using a 0.22 μm filter [13]. 1mL of pre-cleared plasma was placed on a mini-SEC column and eluted with phosphate-buffered saline (PBS)
Summary
Head and neck squamous cell carcinomas (HNSCC) are highly aggressive and immunosuppressive malignancies [1,2,3]. Tcells (Treg ) as opposed to CD8+ effector T cells in the tumor microenvironment (TME) [6,7]. Cancers 2020, 12, 1997 characterized by the expression of ectonucleoside triphosphate diphosphohydrolase-1 (CD39) [8], play an important role in upholding this balance and take part in the production of immune-suppressive factors such as adenosine, a molecule hydrolyzed from adenosine triphosphate (ATP) by CD39 and CD73 through an intermediate step via adenosine diphosphate (ADP) and 50 adenosine monophosphate (AMP). The presence of adenosine in the TME of HNSCC has been linked to tumor progression and poor outcome [9]. Influencing factors on the T cell balance are of great importance to broaden our understanding of tumor-host interaction. Among other mechanisms contributing to immune suppression in the TME of HNSCC, extracellular vesicles (EVs) such as exosomes have been identified as carriers and producers of immunosuppressive molecules
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