miR-130a and miR-145 reprogram Gr-1(+)CD11b(+) myeloid cells and inhibit tumor metastasis through improved host immunity.
miR-130a and miR-145 reprogram Gr-1(+)CD11b(+) myeloid cells and inhibit tumor metastasis through improved host immunity.
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DOI：
10.1038/s41467-018-05023-9
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发表时间：
2018-07-04
影响因子：
16.6
通讯作者：
Yang L
中科院分区：
文献类型：
--
作者：
Ishii H;Vodnala SK;Achyut BR;So JY;Hollander MC;Greten TF;Lal A;Yang L
肿瘤源性可溶性因子促进Gr-1+ CD 11b+未成熟骨髓细胞的产生，TGFβ信号传导在其免疫抑制功能中至关重要。在这里，我们报告了miR-130 a和miR-145直接靶向TGFβ受体II（TβRII），并在这些骨髓细胞中下调，导致TβRII增加。骨髓细胞中miR-130 a和miR-145的异位表达降低了肿瘤转移。这是通过骨髓细胞中2型细胞因子的下调和产生IFNγ的细胞毒性CD 8 T淋巴细胞的增加介导的。miR-130 a和miR-145靶向分子网络（包括TGFβ和IGF 1 R通路）与癌症患者的较高肿瘤分期相关。最后，miR-130 a和miR-145模拟物以及IGF 1 R抑制剂NT 157在临床前小鼠模型中提高了抗肿瘤免疫力并抑制了转移。这些结果表明，miR-130 a和miR-145可以通过改变细胞因子环境和转移微环境来重编程肿瘤相关的骨髓细胞，从而增强宿主的抗肿瘤免疫力。肿瘤产生可溶性因子，其有助于具有TGFβ依赖性免疫抑制功能的Gr-1+ CD 11b+未成熟骨髓细胞的扩增。在这里，作者显示miR-130 a和miR-145靶向TβRII，并通过改变细胞因子微环境，提高抗肿瘤免疫力和抑制临床前小鼠模型中的转移来重新编程这些细胞。
Tumor-derived soluble factors promote the production of Gr-1+CD11b+ immature myeloid cells, and TGFβ signaling is critical in their immune suppressive function. Here, we report that miR-130a and miR-145 directly target TGFβ receptor II (TβRII) and are down-regulated in these myeloid cells, leading to increased TβRII. Ectopic expression of miR-130a and miR-145 in the myeloid cells decreased tumor metastasis. This is mediated through a downregulation of type 2 cytokines in myeloid cells and an increase in IFNγ-producing cytotoxic CD8 T lymphocytes. miR-130a- and miR-145-targeted molecular networks including TGFβ and IGF1R pathways were correlated with higher tumor stages in cancer patients. Lastly, miR-130a and miR-145 mimics, as well as IGF1R inhibitor NT157 improved anti-tumor immunity and inhibited metastasis in preclinical mouse models. These results demonstrated that miR-130a and miR-145 can reprogram tumor-associated myeloid cells by altering the cytokine milieu and metastatic microenvironment, thus enhancing host antitumor immunity. Tumours produce soluble factors that contribute to the expansion of Gr-1+CD11b+ immature myeloid cells with TGFβ dependent immune suppressive function. Here, the authors show miR-130a and miR-145 target TβRII and reprogram these cells by altering the cytokine microenvironment, improving anti-tumour immunity and inhibiting metastasis in preclinical mouse models.
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影响因子：
16.6
作者：
Bronte V;Brandau S;Chen SH;Colombo MP;Frey AB;Greten TF;Mandruzzato S;Murray PJ;Ochoa A;Ostrand-Rosenberg S;Rodriguez PC;Sica A;Umansky V;Vonderheide RH;Gabrilovich DI
通讯作者：
Gabrilovich DI
影响因子：
3.8
作者：
Hong, Chi-Chen;Yao, Song;McCann, Susan E.;Dolnick, Ree Y.;Wallace, Paul K.;Gong, Zhihong;Quan, Lei;Lee, Kelvin P.;Evans, Sharon S.;Repasky, Elizabeth A.;Edge, Stephen B.;Ambrosone, Christine B.
通讯作者：
Ambrosone, Christine B.
影响因子：
21.3
作者：
Baer, Caroline;Squadrito, Mario Leonardo;De Palma, Michele
通讯作者：
De Palma, Michele
DOI：
10.1038/nri2808
发表时间：
2010-08
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
通讯作者：
--
影响因子：
64.8
作者：
Han CZ;Juncadella IJ;Kinchen JM;Buckley MW;Klibanov AL;Dryden K;Onengut-Gumuscu S;Erdbrügger U;Turner SD;Shim YM;Tung KS;Ravichandran KS
通讯作者：
Ravichandran KS