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

V Fleming, X Hu, C Weller, R Weber, C Groth, Z Riester… - Cancer Research, 2019 - AACR
V Fleming, X Hu, C Weller, R Weber, C Groth, Z Riester, L Hüser, Q Sun, V Nagibin
Cancer Research, 2019AACR
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 …
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.
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