Blocking immunosuppressive neutrophils deters pY696-EZH2-driven brain metastases.
Blocking immunosuppressive neutrophils deters pY696-EZH2-driven brain metastases.
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DOI：
10.1126/scitranslmed.aaz5387
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发表时间：
2020-05-27
影响因子：
17.1
通讯作者：
Yu D
中科院分区：
文献类型：
--
作者：
Zhang L;Yao J;Wei Y;Zhou Z;Li P;Qu J;Badu-Nkansah A;Yuan X;Huang YW;Fukumura K;Mao X;Chang WC;Saunus J;Lakhani S;Huse JT;Hung MC;Yu D
The functions of immune cells in brain metastases are unclear because the brain has traditionally been considered “immune privileged.” However, we discovered that a subgroup of immunosuppressive neutrophils is recruited into the brain, enabling brain metastasis development. In brain metastatic cells, enhancer of zeste homologue 2 (EZH2) is highly expressed and phosphorylated at tyrosine-696 (pY696-EZH2) by nuclear-localized Src tyrosine kinase. Phosphorylation of EZH2 at Y696 changes its binding preference from histone H3 to RNA polymerase II, which consequently switches EZH2’s function from a methyltransferase to a transcription factor that increases c-JUN expression. c-Jun upregulates pro-tumorigenic inflammatory cytokines, including granulocyte-colony stimulating factor (G-CSF), which recruits Arg1-positive and PD-L1-positive immunosuppressive neutrophils into the brain to drive metastasis outgrowth. G-CSF-blocking antibodies or immune checkpoint blockade therapies combined with Src inhibitors impeded brain metastasis in multiple mouse models. These findings indicate that pY696-EZH2 can function as a methyltransferase-independent transcription factor to facilitate the brain infiltration of immunosuppressive neutrophils, which could be clinically targeted for brain metastasis treatment. G-CSF antibodies and immune checkpoint blockade with Src inhibitors block neutrophil infiltration to impede pY696-EZH2 driven brain metastasis.
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DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
影响因子：
64.8
作者：
De Henau O;Rausch M;Winkler D;Campesato LF;Liu C;Cymerman DH;Budhu S;Ghosh A;Pink M;Tchaicha J;Douglas M;Tibbitts T;Sharma S;Proctor J;Kosmider N;White K;Stern H;Soglia J;Adams J;Palombella VJ;McGovern K;Kutok JL;Wolchok JD;Merghoub T
通讯作者：
Merghoub T
影响因子：
4.6
作者：
Bae, Woo Kyun;Yoo, Kyung Hyun;Lee, Ji Shin;Kim, Young;Chung, Ik-Joo;Park, Min Ho;Yoon, Jung Han;Furth, Priscilla A.;Hennighausen, Lothar
通讯作者：
Hennighausen, Lothar
影响因子：
16
作者：
Cao, R;Zhang, Y
通讯作者：
Zhang, Y
影响因子：
64.8
作者：
Curtis, Christina;Shah, Sohrab P.;Chin, Suet-Feung;Turashvili, Gulisa;Rueda, Oscar M.;Dunning, Mark J.;Speed, Doug;Lynch, Andy G.;Samarajiwa, Shamith;Yuan, Yinyin;Graef, Stefan;Ha, Gavin;Haffari, Gholamreza;Bashashati, Ali;Russell, Roslin;McKinney, Steven;Langerod, Anita;Green, Andrew;Provenzano, Elena;Wishart, Gordon;Pinder, Sarah;Watson, Peter;Markowetz, Florian;Murphy, Leigh;Ellis, Ian;Purushotham, Arnie;Borresen-Dale, Anne-Lise;Brenton, James D.;Tavare, Simon;Caldas, Carlos;Aparicio, Samuel
通讯作者：
Aparicio, Samuel