Journal
CANCER RESEARCH
Volume 79, Issue 18, Pages 4715-4728Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-19-0053
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Funding
- German Research Council [RTG2099]
- DKFZ-MOST Cooperation in Cancer Research [CA181]
- Italian Association for Cancer Research (IG grant) [18603]
- Italian Association for Cancer Research (Special Program Molecular Clinical Oncology 5 per mille) [12182]
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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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