Biology of Human Tumors Inhibition of Tumor-Derived Prostaglandin-E2 Blocks the Induction ofMyeloid-DerivedSuppressorCells andRecovers Natural Killer Cell Activity

Purpose: Increased frequencies of myeloid-derived suppressor cells (MDSC) correlate with poor prognosis in patients with cancers. Tumor-derived prostaglandin-E2 (PGE2) plays an important role in inducing MDSCs. However, the detailed mechanisms of this induction remain unknown. To develop targeted therapies forMDSCs, we sought to investigate themolecular basis of PGE2-regulated accumulation of MDSCs and their functional consequence on natural killer (NK) cell activity. Experimental Design: The effects of PGE2 in inducing phenotypic, signaling, and functional alternations on monocytes were analyzed in vitro. Suppression of NK-cell activity by PGE2-treated monocytes was compared with that of freshly isolated CD14þHLA-DRlow/ monocytic MDSCs (moMDSC) from patients with melanoma. In addition, to explore the in vivo relevance of targeting PGE2 to reduce MDSC-mediated suppression of NK cells, we established a murine model, where tumor cells were disabled from cyclooxygenase-2 (COX-2) production. Results: Patient-derived moMDSCs inhibited NK-cell activity through the production of TGFb. In vitro, binding of PGE2 to EP2 and EP4 receptors onmonocytes activated the p38MAPK/ERKpathway and resulted in elevated secretion of TGFb. Similar to moMDSCs, PGE2-treated monocytes potently suppressed NK-cell activity through production of TGFb. Furthermore, silencing COX-2 in murine 4T1 tumor cells reduced the accumulation of CD11bþGr1þMDSCs in the spleen, resulting in concomitant improved in vivo clearance of NK-cell sensitive YAC-1 cells. Conclusions: Our results reveal an indispensable role of tumor-derived PGE2 in inducing MDSCs and suggest a favorable outcomeof combiningCOX-2–targeted therapy andadoptiveNK-cell transfer in patients with cancer. Clin Cancer Res; 20(15); 4096–106. 2014 AACR.