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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| Hauptverfasser: | , , , , , , , , , , , , , |
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| Dokumenttyp: | Article (Journal) |
| Sprache: | Englisch |
| Veröffentlicht: |
July 23, 2019
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| In: |
Cancer research
Year: 2019, Jahrgang: 79, Heft: 18, Pages: 4715-4728 |
| ISSN: | 1538-7445 |
| DOI: | 10.1158/0008-5472.CAN-19-0053 |
| Online-Zugang: | Verlag, Volltext: http://dx.doi.org/10.1158/0008-5472.CAN-19-0053
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| Verfasserangaben: | 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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| 245 | 1 | 0 | |a Melanoma extracellular vesicles generate immunosuppressive myeloid cells by ipregulating PD-L1 via TLR4 signaling |c 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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| 520 | |a 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. | ||
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