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| Home > Publications database > Melanoma extracellular vesicles generate immunosuppressive myeloid cells by PD-L1 upregulation via TLR4 signaling. |
| Home > Publications database > Melanoma extracellular vesicles generate immunosuppressive myeloid cells by PD-L1 upregulation via TLR4 signaling. |
| Journal Article | DKFZ-2019-01912 |
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2019
AACR
Philadelphia, Pa.
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Please use a persistent id in citations: doi:10.1158/0008-5472.CAN-19-0053
Abstract: Tumor cell-derived extracellular vesicles (EV) convert normal myeloid cells into myeloid-derived suppressor cells (MDSC), inhibiting anti-tumor 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, this effect was dependent on heat-shock protein 86 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.
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