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Melanoma extracellular vesicles generate immunosuppressive myeloid cells by ipregulating PD-L1 via TLR4 signaling

Tumor cell-derived extracellular vesicles (EV) convert normal myeloid cells into myeloid-derived suppressor cells (MDSC), inhibiting antitumor immune responses. Here, we show that EV from Ret mouse melanoma cells upregulate the expression of programmed cell death ligand 1 (PD-L1) on mouse immature m...

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Main Authors: Fleming, Viktor (Author) , Hu, Xiaoying (Author) , Weller, Céline (Author) , Bitsch, Rebekka (Author) , Groth, Christopher (Author) , Riester, Zeno (Author) , Hüser, Laura (Author) , Sun, Qian (Author) , Nagibin, Vasyl (Author) , Kirschning, Carsten (Author) , Bronte, Vincenzo (Author) , Utikal, Jochen (Author) , Altevogt, Peter (Author) , Umansky, Viktor (Author)
Format: Article (Journal)
Language:English
Published: July 23, 2019
In: Cancer research
Year: 2019, Volume: 79, Issue: 18, Pages: 4715-4728
ISSN:1538-7445
DOI:10.1158/0008-5472.CAN-19-0053
Online Access:Verlag, Volltext: http://dx.doi.org/10.1158/0008-5472.CAN-19-0053
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Author Notes:Viktor Fleming, Xiaoying Hu, Céline Weller, Rebekka Weber, Christopher Groth, Zeno Riester, Laura Hüser, Qian Sun, Vasyl Nagibin, Carsten Kirschning, Vincenzo Bronte, Jochen Utikal, Peter Altevogt, and Viktor Umansky
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Summary:Tumor cell-derived extracellular vesicles (EV) convert normal myeloid cells into myeloid-derived suppressor cells (MDSC), inhibiting antitumor immune responses. Here, we show that EV from Ret mouse melanoma cells upregulate the expression of programmed cell death ligand 1 (PD-L1) on mouse immature myeloid cells (IMC), leading to suppression of T-cell activation. PD-L1 expression and the immunosuppressive potential of EV-generated MDSC were dependent on the expression of Toll-like receptors (TLR). IMC from Tlr4-/- mice failed to increase T-cell PD-L1 expression and immunosuppression with Ret-EV treatment, and this effect was dependent on heat-shock protein 86 (HSP86) as HSP86-deficient Ret cells could not stimulate PD-L1 expression on normal IMC; IMC from Tlr2-/- and Tlr7-/- mice demonstrated similar results, although to a lesser extent. HSP86-deficient Ret cells slowed tumor progression in vivo associated with decreased frequency of tumor-infiltrating PD-L1+CD11b+Gr1+ MDSC. EV from human melanoma cells upregulated PD-L1 and immunosuppression of normal monocytes dependent on HSP86. These findings highlight a novel EV-mediated mechanism of MDSC generation from normal myeloid cells, suggesting the importance of EV targeting for tumor therapy. SIGNIFICANCE: These findings validate the importance of TLR4 signaling in reprogramming normal myeloid cells into functional myeloid-derived suppressor cells.
Item Description:Gesehen am 27.02.2020
Physical Description:Online Resource
ISSN:1538-7445
DOI:10.1158/0008-5472.CAN-19-0053

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