miR-21 depletion in macrophages promotes tumoricidal polarization and enhances PD-1 immunotherapy.
miR-21 depletion in macrophages promotes tumoricidal polarization and enhances PD-1 immunotherapy.
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巨噬细胞中miR-21的缺失促进肿瘤杀伤极化并增强PD-1免疫治疗。
DOI：
10.1038/s41388-018-0178-3
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发表时间：
2018-06
期刊：
影响因子：
8
通讯作者：
Li Y
中科院分区：
文献类型：
--
作者：
Xi J;Huang Q;Wang L;Ma X;Deng Q;Kumar M;Zhou Z;Li L;Zeng Z;Young KH;Zhang M;Li Y
MicroRNA-21 (miR-21) 是哺乳动物细胞中最丰富的 microRNA 之一。它在调节细胞凋亡和致癌转化中的作用已被深入研究。然而，miR-21对宿主抗肿瘤免疫的影响仍不清楚。肿瘤相关巨噬细胞是一种主要的白细胞类型，可浸润肿瘤并主要发育成免疫抑制性、肿瘤促进性 M2 样巨噬细胞。相反，促炎性 M1 样巨噬细胞具有杀肿瘤活性。在这项研究中，我们发现，在体内和体外肿瘤细胞存在的情况下，miR-21 的遗传缺陷会促进巨噬细胞向 M1 样表型极化；因此，它赋予宿主小鼠增强的抗肿瘤免疫力。通过下调 JAK2 和 STAT1，miR-21 抑制 IFN-γ 诱导的 STAT1 信号通路，这是巨噬细胞 M1 极化所需的。我们还表明，巨噬细胞中 miR-21 的表达受到极化刺激以及巨噬细胞与肿瘤细胞共培养的调节。因此，肿瘤细胞可能会刺激肿瘤相关巨噬细胞中的 miR-21 表达，以防止杀伤肿瘤的 M1 极化。然而，miR-21 缺陷介导的 STAT1 信号增强会上调巨噬细胞中的 PD-L1 表达，从而抑制吞噬细胞的抗肿瘤活性。这种不良反应可以通过PD-1阻断来缓解；事实上，巨噬细胞中的 miR-21 消耗和 PD-1 抗体治疗比单独使用任何一种药物都具有更好的抗肿瘤活性。这些研究揭示了结合 miR-21 抑制和免疫检查点阻断来靶向肿瘤微环境的潜在应用。
MicroRNA-21 (miR-21) is one of the most abundant microRNAs in mammalian cells. It has been intensively studied for its role in regulating apoptosis and oncogenic transformation. However, the impact of miR-21 on host anti-tumor immunity remains unknown. Tumor-associated macrophages are a major leukocyte type that infiltrates tumors and predominantly develops into immunosuppressive, tumor-promoting M2-like macrophages. In contrast, the pro-inflammatory M1−like macrophages have tumoricidal activity. In this study, we show that genetic deficiency of miR-21 promotes the polarization of macrophages toward an M1-like phenotype in vivo and in vitro in the presence of tumor cells; thus it confers host mice with enhanced anti-tumor immunity. By downregulating JAK2 and STAT1, miR-21 inhibits the IFN-γ-induced STAT1 signaling pathway, which is required for macrophage M1 polarization. We also show that the expression of miR-21 in macrophages is regulated upon polarization stimuli as well as upon macrophages co-culturing with tumor cells. Thus, tumor cells may stimulate miR-21 expression in tumor-associated macrophages to prevent tumoricidal M1 polarization. However, augmented STAT1 signaling mediated by miR-21 deficiency upregulates PD-L1 expression in macrophages, which is known to inhibit phagocytic anti-tumor activity. This adverse effect can be alleviated by PD-1 blockade; indeed, miR-21 depletion in macrophages and PD-1 antibody treatment offer superior anti-tumor activity than either agent alone. These studies shed lights on potential application of the combination of miR-21 inhibition and immune checkpoint blockade to target the tumor microenvironment.
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影响因子：
56.9
作者：
Lagos-Quintana, M;Rauhut, R;Tuschl, T
通讯作者：
Tuschl, T
DOI：
10.1158/1078-0432.ccr-12-1281
发表时间：
2013-04-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Jahangiri A;De Lay M;Miller LM;Carbonell WS;Hu YL;Lu K;Tom MW;Paquette J;Tokuyasu TA;Tsao S;Marshall R;Perry A;Bjorgan KM;Chaumeil MM;Ronen SM;Bergers G;Aghi MK
通讯作者：
Aghi MK
致癌 miR-21 microRNA 与 p53 肿瘤抑制通路的相互作用
影响因子：
4.7
作者：
Ma, Xiaodong;Choudhury, Saibyasachi N.;Li, Yong
通讯作者：
Li, Yong
影响因子：
21.3
作者：
Baer, Caroline;Squadrito, Mario Leonardo;De Palma, Michele
通讯作者：
De Palma, Michele
影响因子：
32.4
作者：
Haverkamp, Jessica M.;Smith, Amber M.;Weinlich, Ricardo;Dillon, Christopher P.;Qualls, Joseph E.;Neale, Geoffrey;Koss, Brian;Kim, Young;Bronte, Vincenzo;Herold, Marco J.;Green, Douglas R.;Opferman, Joseph T.;Murray, Peter J.
通讯作者：
Murray, Peter J.