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

• Verfasst von: Fleming, Viktor [VerfasserIn]
• Verfasst von: Hu, Xiaoying [VerfasserIn]
• Verfasst von: Weller, Céline [VerfasserIn]
• Verfasst von: Weber, Rebekka [VerfasserIn]
• Verfasst von: Groth, Christopher [VerfasserIn]
• Verfasst von: Riester, Zeno [VerfasserIn]
• Verfasst von: Hüser, Laura [VerfasserIn]
• Verfasst von: Sun, Qian [VerfasserIn]
• Verfasst von: Nagibin, Vasyl [VerfasserIn]
• Verfasst von: Kirschning, Carsten [VerfasserIn]
• Verfasst von: Bronte, Vincenzo [VerfasserIn]
• Verfasst von: Utikal, Jochen [VerfasserIn]
• Verfasst von: Altevogt, Peter [VerfasserIn]
• Verfasst von: Umansky, Viktor [VerfasserIn]
• Titel: Melanoma extracellular vesicles generate immunosuppressive myeloid cells by ipregulating PD-L1 via TLR4 signaling
• Verf.angabe: 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
• E-Jahr: 2019
• Jahr: July 23, 2019
• Umfang: 14 S.
• Fussnoten: Gesehen am 27.02.2020
• Titel Quelle: Enthalten in: Cancer research
• Ort Quelle: Philadelphia, Pa. : AACR, 1916
• Jahr Quelle: 2019
• Band/Heft Quelle: 79(2019), 18, Seite 4715-4728
• ISSN Quelle: 1538-7445
• DOI: doi:10.1158/0008-5472.CAN-19-0053
• Datenträger: Online-Ressource
• Sprache: eng
• K10plus-PPN: 1691158429

Abstract

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.