Suppression of microRNA activity amplifies IFN-γ-induced macrophage activation and promotes anti-tumour immunity
Suppression of microRNA activity amplifies IFN-γ-induced macrophage activation and promotes anti-tumour immunity
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DOI：
10.1038/ncb3371
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发表时间：
2016-07-01
影响因子：
21.3
通讯作者：
De Palma, Michele
中科院分区：
文献类型：
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作者：
Baer, Caroline;Squadrito, Mario Leonardo;De Palma, Michele
肿瘤相关巨噬细胞（TAM）主要表达交替激活（或M2）表型，这需要免疫抑制和肿瘤促进能力。将TAM重编程为经典活化（M1）表型可能会阻碍肿瘤相关的免疫抑制并释放抗肿瘤免疫力。在这里，我们表明，有条件的删除microRNA（miRNA）-加工酶DICER在巨噬细胞提示M1样TAM编程，其特征是过度活跃的IFN-γ/STAT 1信号。这种重新连接减弱了TAM的免疫抑制能力，并促进了激活的细胞毒性T淋巴细胞（CTL）向肿瘤的募集。CTL衍生的IFN-γ加剧Dicer 1缺陷TAM的M1极化并抑制肿瘤生长。值得注意的是，TAM中的DICER缺陷否定了抗CSF 1 R抗体对巨噬细胞消耗的抗肿瘤作用，并使PD 1检查点阻断或CD 40激动性抗体能够完全根除肿瘤。最后，Dicer 1缺陷TAM中Let-7 miRNA活性的遗传拯救部分恢复了它们的M2样表型，并减少了肿瘤浸润性CTL。这些发现表明，DICER/Let-7活性对抗IFN-γ诱导的免疫刺激性M1样TAM活化，具有潜在的治疗意义。
Tumour-associated macrophages (TAMs) largely express an alternatively activated (or M2) phenotype, which entails immunosuppressive and tumour-promoting capabilities. Reprogramming TAMs towards a classically activated (M1) phenotype may thwart tumour-associated immunosuppression and unleash anti-tumour immunity. Here we show that conditional deletion of the microRNA (miRNA)-processing enzyme DICER in macrophages prompts M1-like TAM programming, characterized by hyperactive IFN-gamma/STAT1 signalling. This rewiring abated the immunosuppressive capacity of TAMs and fostered the recruitment of activated cytotoxic T lymphocytes (CTLs) to the tumours. CTL-derived IFN-gamma exacerbated M1 polarization of Dicer1-deficient TAMs and inhibited tumour growth. Remarkably, DICER deficiency in TAMs negated the anti-tumoral effects of macrophage depletion by anti-CSF1R antibodies, and enabled complete tumour eradication by PD1 checkpoint blockade or CD40 agonistic antibodies. Finally, genetic rescue of Let-7 miRNA activity in Dicer1-deficient TAMs partly restored their M2-like phenotype and decreased tumour-infiltrating CTLs. These findings suggest that DICER/Let-7 activity opposes IFN-gamma-induced, immunostimulatory M1-like TAM activation, with potential therapeutic implications.