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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.
Highlights
Melanoma belongs to the group of tumors that are highly sensitive to immunotherapies.The therapeutic antibodies targeting the immune checkpoints, ipilimumab for cytotoxic T-lymphocyte antigen-4 (CTLA-4) and nivolumab and pembrolizumab for programmed death 1 (PD-1), greatly increased the average life expectancy for patients with metastatic melanoma
The activation of cytotoxic T cells depends on their direct interactions with antigen presenting cells (APCs) which take up tumor-associated antigens (TAA), process them into peptides, and present them on major histocompatibility complex (MHC)
Melanoma cell lines were grown in serum-free (DMBC cell lines) or exosome-depleted medium (A375) and small extracellular vesicles (sEVs) were isolated by differential centrifugation
Summary
Melanoma belongs to the group of tumors that are highly sensitive to immunotherapies.The therapeutic antibodies targeting the immune checkpoints, ipilimumab for cytotoxic T-lymphocyte antigen-4 (CTLA-4) and nivolumab and pembrolizumab for programmed death 1 (PD-1), greatly increased the average life expectancy for patients with metastatic melanoma. The activation of cytotoxic T cells depends on their direct interactions with antigen presenting cells (APCs) which take up tumor-associated antigens (TAA), process them into peptides, and present them on MHC 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. 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. 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
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