DNA methyltransferase inhibition upregulates MHC-I to potentiate cytotoxic T lymphocyte responses in breast cancer.
DNA methyltransferase inhibition upregulates MHC-I to potentiate cytotoxic T lymphocyte responses in breast cancer.
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DOI：
10.1038/s41467-017-02630-w
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发表时间：
2018-01-16
影响因子：
16.6
通讯作者：
Balko JM
中科院分区：
文献类型：
--
作者：
Luo N;Nixon MJ;Gonzalez-Ericsson PI;Sanchez V;Opalenik SR;Li H;Zahnow CA;Nickels ML;Liu F;Tantawy MN;Sanders ME;Manning HC;Balko JM
通过诱导肿瘤炎症和T细胞介导的应答来增强抗肿瘤免疫是癌症治疗的一个有前途的领域。促进这些效应的免疫调节剂通过多种机制发挥作用，包括上调抗原呈递途径。在这里，我们表明，主要组织相容性I类（MHC-I）基因在人类乳腺癌中甲基化，抑制其表达。用下一代低甲基化剂guadecitabine治疗乳腺癌细胞系可上调干扰素-γ应答的MHC-I表达在乳腺癌的鼠肿瘤模型中，胍地他滨上调肿瘤细胞中的MHC-I，促进CD 8 + T细胞向微环境的募集。最后，我们表明，MHC-I基因在乳腺癌患者用低甲基化剂治疗上调。因此，低甲基化剂的免疫调节作用可能涉及上调I类抗原呈递以增强CD 8 + T细胞应答。这些策略可能有助于增强免疫难治性乳腺癌的抗肿瘤免疫力和对检查点抑制的反应。免疫疗法作为癌症的单一选择治疗往往失败。在这里，作者表明，靶向DNA甲基转移酶，如DNMT 1，可以通过增加MHC基因表达和CD 8 + T细胞的募集来增强抗肿瘤免疫力和对检查点抑制的反应。
Potentiating anti-tumor immunity by inducing tumor inflammation and T cell-mediated responses are a promising area of cancer therapy. Immunomodulatory agents that promote these effects function via a wide variety of mechanisms, including upregulation of antigen presentation pathways. Here, we show that major histocompatibility class-I (MHC-I) genes are methylated in human breast cancers, suppressing their expression. Treatment of breast cancer cell lines with a next-generation hypomethylating agent, guadecitabine, upregulates MHC-I expression in response to interferon-γ. In murine tumor models of breast cancer, guadecitabine upregulates MHC-I in tumor cells promoting recruitment of CD8+ T cells to the microenvironment. Finally, we show that MHC-I genes are upregulated in breast cancer patients treated with hypomethylating agents. Thus, the immunomodulatory effects of hypomethylating agents likely involve upregulation of class-I antigen presentation to potentiate CD8+ T cell responses. These strategies may be useful to potentiate anti-tumor immunity and responses to checkpoint inhibition in immune-refractory breast cancers. Immunotherapy often fails as a single option treatment in cancer. Here, the authors show that targeting of DNA methyltransferases, such as DNMT1, can potentiate anti-tumor immunity and response to checkpoint inhibition by increasing MHC gene expression and the recruitment of CD8+ T cells.
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DOI：
10.1158/1078-0432.ccr-15-1125
发表时间：
2016-03-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Loi S;Dushyanthen S;Beavis PA;Salgado R;Denkert C;Savas P;Combs S;Rimm DL;Giltnane JM;Estrada MV;Sánchez V;Sanders ME;Cook RS;Pilkinton MA;Mallal SA;Wang K;Miller VA;Stephens PJ;Yelensky R;Doimi FD;Gómez H;Ryzhov SV;Darcy PK;Arteaga CL;Balko JM
通讯作者：
Balko JM
募集高危险性CD8（+）T细胞的潜在池募集到抗肿瘤免疫反应中。
DOI：
10.1084/jem.20042167
发表时间：
2005-05-16
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Ercolini AM;Ladle BH;Manning EA;Pfannenstiel LW;Armstrong TD;Machiels JP;Bieler JG;Emens LA;Reilly RT;Jaffee EM
通讯作者：
Jaffee EM
影响因子：
32.4
作者：
Ebert, Peter J. R.;Cheung, Jeanne;Mellman, Ira
通讯作者：
Mellman, Ira
影响因子：
11.4
作者：
通讯作者：
--
影响因子：
64.5
作者：
Rooney MS;Shukla SA;Wu CJ;Getz G;Hacohen N
通讯作者：
Hacohen N