Inhibition of Tumor-Derived Prostaglandin-E2 Blocks the Induction of Myeloid-Derived Suppressor Cells and Recovers Natural Killer Cell Activity
Inhibition of Tumor-Derived Prostaglandin-E2 Blocks the Induction of Myeloid-Derived Suppressor Cells and Recovers Natural Killer Cell Activity
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DOI：
10.1158/1078-0432.ccr-14-0635
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发表时间：
2014-08-01
影响因子：
11.5
通讯作者：
Lundqvist, Andreas
中科院分区：
文献类型：
--
作者：
Mao, Yumeng;Sarhan, Dhifaf;Lundqvist, Andreas
目的：髓源性抑制细胞（MDSC）频率增加与癌症患者预后不良相关。肿瘤来源的前列腺素E2（PGE2）在诱导MDSCs中起重要作用。然而，这种诱导的详细机制仍然未知。为了开发MDSCs的靶向治疗，我们试图研究PGE2调节MDSCs积累的分子基础及其对自然杀伤（NK）细胞活性的功能后果。实验设计：体外分析PGE2诱导单核细胞表型、信号传导和功能改变的作用。将PGE2处理的单核细胞对NK细胞活性的抑制与从黑素瘤患者新鲜分离的CD14（+）HLA-DR低/-单核MDSC（moMDSC）的抑制进行比较。此外，为了探索靶向PGE2以减少MDSC介导的NK细胞抑制的体内相关性，我们建立了小鼠模型，其中肿瘤细胞不能产生环氧合酶-2（考克斯-2）。在体外，PGE2与单核细胞上的EP2和EP4受体结合激活了p38 MAPK/ERK通路，并导致TGF β分泌增加。与moMDSC类似，PGE 2处理的单核细胞通过产生TGF β有效抑制NK细胞活性。此外，小鼠4T1肿瘤细胞中的考克斯-2沉默减少了脾脏中CD11b（+）Gr1（+）MDSC的积累，导致NK细胞敏感性YAC-1细胞的体内清除率同时提高。我们的研究结果揭示了肿瘤源性PGE 2在诱导MDSC中的不可或缺的作用，并表明在癌症患者中结合考克斯-2靶向治疗和过继NK细胞转移的良好结果。(C)2014年AACR。
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 for MDSCs, we sought to investigate the molecular 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 CD14(+)HLA-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 TGF beta. In vitro, binding of PGE2 to EP2 and EP4 receptors on monocytes activated the p38MAPK/ERK pathway and resulted in elevated secretion of TGF beta. Similar to moMDSCs, PGE2-treated monocytes potently suppressed NK-cell activity through production of TGF beta. Furthermore, silencing COX-2 in murine 4T1 tumor cells reduced the accumulation of CD11b(+)Gr1(+) MDSCs 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 outcome of combining COX-2-targeted therapy and adoptive NK-cell transfer in patients with cancer. (C) 2014 AACR.