Evasion of antitumor immunity and immunotherapy by melanoma extracellular vesicl...
Melanoma is the deadliest of the skin cancers. Immune checkpoint inhibitors (ICI), which are blocking antibodies that help to restore antitumor immunity, are currently used for the treatment of metastatic melanoma. However, only a...
Melanoma is the deadliest of the skin cancers. Immune checkpoint inhibitors (ICI), which are blocking antibodies that help to restore antitumor immunity, are currently used for the treatment of metastatic melanoma. However, only approximately 20% of the patients respond to ICI. Understanding the molecular mechanisms behind the resistance to these therapies is essential to predict patients' response and increase treatment success. Extracellular vesicles(EVs), nanosized structures released by virtually all cells, are key mediators of cell-cell communication and horizontal transfer of biomolecules locally and systemically. EVs are known to play an important role in cancer biology by regulating cell apoptosis, angiogenesis, antigen presentation and immune modulation. In recent years, EVs have been shown to also act as protein-decoys, through binding and sequestering soluble proteins, thus preventing protein-target interactions. Previous work from the host group shows that EVs excreted by melanoma cell lines express interferon-γ receptor (IFNGR). Thus, we hypothesize that melanoma-derived EVs modulate the bioavailability and activity of this cytokine. Preliminary results show that EVs isolated from mouse metastatic melanoma B16-F10 cells express IFNGR, bind to IFNγ, and protect tumor cells from the cytotoxic effect of IFNγ. Because resistance to antitumor immunity and to ICI has been linked to defects in IFNγ signaling, this project aims to investigate whether IFNGR+ EVs downregulate IFNγ signaling and ICI response. This research has the potential to unveil a novel yet overlooked cancer immune evasion mechanism mediated by IFNGR+ EVs, which may provide crucial insights to optimize current cancer therapies and ultimately improve patient outcomes.ver más
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