Tumor-Derived Prostaglandin E2 Promotes p50 NF-κB-Dependent Differentiation of Monocytic MDSCs
Tumor-Derived Prostaglandin E2 Promotes p50 NF-κB-Dependent Differentiation of Monocytic MDSCs
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DOI：
10.1158/0008-5472.can-19-2843
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发表时间：
2020-07-01
期刊：
影响因子：
11.2
通讯作者：
Sica, Antonio
中科院分区：
文献类型：
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作者：
Porta, Chiara;Consonni, Francesca Maria;Sica, Antonio
骨髓源性抑制细胞（MDSC）包括未成熟单核细胞（M-MDSC）和粒细胞（PMN-MDSC）细胞，它们具有抑制适应性免疫和阻碍抗癌治疗有效性的能力。值得注意的是，响应于IFN γ，M-MDSC释放肿瘤促进和免疫抑制分子一氧化氮（NO），而巨噬细胞主要表达抗肿瘤特性。研究这些相反的活性，我们发现肿瘤衍生的前列腺素E2（PGE 2）诱导M-MDSC中p50 NF-κ B B的核积累，将它们对IFN γ的反应转向NO介导的免疫抑制并降低TNF α表达。在基因组水平，p50 NF-κ B促进STAT 1与选定的IFN γ依赖性基因的调节区结合，包括诱导型一氧化氮合酶（Nos 2）。一致的是，p50的消融以及PGE 2受体EP 2或NO产生的药理学抑制将M-MDSC重编程为NOS 2（低）/TNE α（高）表型，恢复IFNT的体内抗肿瘤活性。我们的研究结果表明，抑制PGE 2/p50/NO轴阻止MDSC抑制功能和恢复抗癌immunotherapy.Significance肿瘤衍生的PGE 2介导的诱导核p50 NF-κ B表观遗传学重新编程的单核细胞对IFN γ的反应，对免疫抑制表型，从而检索IFN γ的抗癌特性。[图形]。
Myeloid-derived suppressor cells (MDSC) include immature monocytic (M-MDSC) and granulocytic (PMN-MDSC) cells that share the ability to suppress adaptive immunity and to hinder the effectiveness of anticancer treatments. Of note, in response to IFN gamma, M-MDSCs release the tumor-promoting and immunosuppressive molecule nitric oxide (NO), whereas macrophages largely express antitumor properties. Investigating these opposing activities, we found that tumor-derived prostaglandin E2 (PGE2) induces nuclear accumulation of p50 NF-kappa B in M-MDSCs, diverting their response to IFN gamma toward NO-mediated immunosuppression and reducing TNF alpha expression. At the genome level, p50 NF-kappa B promoted binding of STAT1 to regulatory regions of selected IFN gamma-dependent genes, including inducible nitric oxide synthase (Nos2). In agreement, ablation of p50 as well as pharmacologic inhibition of either the PGE2 receptor EP2 or NO production reprogrammed M-MDSCs toward a NOS2(low)/TNE alpha(high) phenotype, restoring the in vivo antitumor activity of IFNT. Our results indicate that inhibition of the PGE2/p50/NO axis prevents MDSC-suppressive functions and restores the efficacy of anticancer immunotherapy.Significance Tumor-derived PGE2-mediated induction of nuclear p50 NF-kappa B epigenetically reprograms the response of monocytic cells to IFN gamma toward an immunosuppressive phenotype, thus retrieving the anticancer properties of IFN gamma.[GRAPHICS].