Usp18 deficient mammary epithelial cells create an antitumour environment driven by hypersensitivity to IFN-λ and elevated secretion of Cxcl10.
Usp18 deficient mammary epithelial cells create an antitumour environment driven by hypersensitivity to IFN-λ and elevated secretion of Cxcl10.
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DOI：
10.1002/emmm.201201864
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发表时间：
2013-07
影响因子：
11.1
通讯作者：
Zhang, Dong-Er
中科院分区：
文献类型：
--
作者：
Burkart, Christoph;Arimoto, Kei-ichiro;Tang, Tingdong;Cong, Xiuli;Xiao, Nengming;Liu, Yun-Cai;Kotenko, Sergei V.;Ellies, Lesley G.;Zhang, Dong-Er
癌症免疫编辑理论是指免疫系统可以抑制或促进肿瘤进展的机制。开发新型癌症免疫疗法的一个主要挑战是找到利用免疫系统的抗肿瘤活性同时降低其促肿瘤活性的方法。使用乳腺肿瘤发生的PyVmT模型，我们表明缺乏Usp 18基因通过创建肿瘤抑制微环境来显著抑制肿瘤生长。这种抗肿瘤环境的产生是由Usp 18缺陷型乳腺上皮细胞（MEC）分泌的强效T细胞化学引诱物Cxcl 10升高驱动的，这导致Th 1亚型CD 4 + T细胞的募集。此外，我们发现，Cxcl 10在MEC中的上调是由干扰素-λ促进的，并且Usp 18是干扰素-λ信号传导的新型抑制剂。干扰素-λ特异性受体亚基IL-28 R1在Usp 18缺陷MEC中的敲低显著增强肿瘤生长。总之，我们的数据表明，靶向Usp 18可能是一种可行的方法，可以提高抗肿瘤免疫力，同时抑制免疫系统的促肿瘤活性。
The theory of cancer immunoediting refers to mechanisms by which the immune system can suppress or promote tumour progression. A major challenge for the development of novel cancer immunotherapies is to find ways to exploit the immune system's antitumour activity while concomitantly reducing its protumour activity. Using the PyVmT model of mammary tumourigenesis, we show that lack of the Usp18 gene significantly inhibits tumour growth by creating a tumour-suppressive microenvironment. Generation of this antitumour environment is driven by elevated secretion of the potent T-cell chemoattractant Cxcl10 by Usp18 deficient mammary epithelial cells (MECs), which leads to recruitment of Th1 subtype CD4+ T cells. Furthermore, we show that Cxcl10 upregulation in MECs is promoted by interferon-λ and that Usp18 is a novel inhibitor of interferon-λ signalling. Knockdown of the interferon-λ specific receptor subunit IL-28R1 in Usp18 deficient MECs dramatically enhances tumour growth. Taken together, our data suggest that targeting Usp18 may be a viable approach to boost antitumour immunity while suppressing the protumour activity of the immune system.
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影响因子：
30.5
作者：
Dunn, GP;Bruce, AT;Schreiber, RD
通讯作者：
Schreiber, RD
DOI：
10.1073/pnas.0901329106
发表时间：
2009-06-02
影响因子：
11.1
作者：
Critchley-Thorne, Rebecca J.;Simons, Diana L.;Lee, Peter P.
通讯作者：
Lee, Peter P.
影响因子：
15.9
作者：
Chiang, Jeffrey Y.;Jang, Ihn Kyung;Gu, Hua
通讯作者：
Gu, Hua
影响因子：
15.3
作者：
Bonecchi, R;Bianchi, G;Bordignon, P P;D'Ambrosio, D;Lang, R;Borsatti, A;Sozzani, S;Allavena, P;Gray, P A;Mantovani, A;Sinigaglia, F
通讯作者：
Sinigaglia, F
影响因子：
3.7
作者：
François-Newton V;Magno de Freitas Almeida G;Payelle-Brogard B;Monneron D;Pichard-Garcia L;Piehler J;Pellegrini S;Uzé G
通讯作者：
Uzé G