Melanoma-Derived Extracellular Vesicles Bear the Potential for the Induction of Antigen-Specific Tolerance

Abstract

Background: Cancer-induced immunosuppression is antigen-specific rather than systemic and the mechanisms for the antigen specificity are incompletely understood. Here we explore the option that tumor-associated antigens (TAAs) may be transferred to antigen-presenting cells (APCs), together with immunosuppressive molecules, through cancer-derived small extracellular vesicles (sEVs), such as exosomes. Stimulation of a suppressive phenotype in the very same APCs that take up TAAs may yield antigen-specific tolerance. Methods: sEVs isolated from patient-derived or well-established melanoma cell lines were used to demonstrate the transfer of major histocompatibility complex (MHC) molecules to the surface of APCs. The immunosuppressive influence of sEVs was assessed by flow cytometry analysis of activation markers, cytokine expression, and mixed lymphocyte reactions. Results: MHC class I molecules were transferred from melanoma cells to the cell surface of APCs by sEVs. Concomitantly, CD86 and CD40 co-stimulatory molecules were down-regulated and IL-6 production was strongly induced. TGF-β transported by sEVs contributed to the promotion of a suppressive phenotype of APCs. Conclusion: The presented results indicate the existence of a hitherto undescribed mechanism that offers an explanation for antigen-specific tolerance induction mediated by cancer-derived sEVs.

Exosomes as Messengers between Mother and Fetus in Pregnancy

“…Cancer-derived exosomes prevent the differentiation and activation of immune effector cells, modulate antigen expression, induce T cell apoptosis, and transport immunosuppressive cytokines. Recently, we provided evidence that melanoma-derived EVs were able to confer antigen-specific immunosuppression by simultaneously transporting MHC molecules presenting cancer-specific antigenic peptides and immunosuppressive cytokines [48]. Antigen-specific immunosuppression seems to occur during pregnancy as well and could be partially mediated by EVs.…”

Signaling of Tumor-Derived sEV Impacts Melanoma Progression

“…The in-depth knowledge of the pleiotropic role of MTEX in the natural history of melanoma has a great potential clinical application in the disease diagnosis, treatment design, and prognosis of patient’s outcomes. MTEX are involved in a plethora of functions involved in initiation, progression, and metastasis of tumors, which is schematically depicted in Figure 2 (according to [ 26 , 37 , 73 , 74 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 , 92 , 93 , 94 , 95 , 96 , 97 , 98 , 99 , 100 , 101 , 102 , 103 , 104 , 105 , 106 , 107 , 108 , 109 , 110 , 111 , 112 , 113 , 114 , 115 , 116 , 117 , 118 , 119 , 120 , 121 , 122 , 123 , 124 , 125 , 126 , 127 , 128 , 129 , 130 , 131 ,…”

“…However, in most of the studies reported in this context, melanoma cell lines were used as a source of MTEX. Düchler et al showed that cancer-induced immunosuppression was mediated by MTEX, and involved an antigen-specific mechanism [ 118 ]. The authors provided evidence that MTEX transferred MHC class I receptor proteins from cancer cells to the surface of antigen-presenting cells (APC).…”

“…Collaboration of TGF-β transported by MTEX was also demonstrated in this process. The authors hypothesized that MTEX-mediated transfer of the combination of TAA-derived peptide-MHC complexes with immunosuppressive cytokines was a part of antigen-specific tolerance induction enabling melanoma immune escape [ 118 ]. The mechanism of melanoma immune escape is also related to the suppression of T cell functions.…”

Extracellular vesicle-mediated crosstalk between melanoma and the immune system: Impact on tumor progression and therapy response

“…1). Düchler and colleagues used EVs derived from A375 human metastatic melanoma cells and observed different effects depending on the dendritic cell model used but down‐regulation of HLA class I and II was commonly observed 50 . They also showed that these melanoma‐derived EVs transfer HLA class I and TGF‐β to DCs, and the latter would be key to the immunosuppressive modulation observed 50 (Fig.…”