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DNA methyltransferase inhibition upregulates MHC-I to potentiate cytotoxic T lymphocyte responses in breast cancer.
Nature Communications ( IF 14.7 ) Pub Date : 2018-01-16 , DOI: 10.1038/s41467-017-02630-w
Na Luo , Mellissa J. Nixon , Paula I. Gonzalez-Ericsson , Violeta Sanchez , Susan R. Opalenik , Huili Li , Cynthia A. Zahnow , Michael L. Nickels , Fei Liu , Mohammed N. Tantawy , Melinda E. Sanders , H. Charles Manning , Justin M. Balko

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.

中文翻译:

DNA甲基转移酶抑制作用上调MHC-1以增强乳腺癌中的细胞毒性T淋巴细胞反应。

通过诱导肿瘤炎症和T细胞介导的反应来增强抗肿瘤免疫力是癌症治疗的一个有希望的领域。促进这些作用的免疫调节剂通过多种机制起作用,包括抗原呈递途径的上调。在这里,我们显示了主要的组织相容性I类(MHC-1)基因在人类乳腺癌中被甲基化,从而抑制了它们的表达。用下一代次甲基化剂瓜地他滨治疗乳腺癌细胞系可上调MHC-1的表达,以响应干扰素-γ。在乳腺癌的鼠类肿瘤模型中,瓜地他滨上调肿瘤细胞中的MHC-1,从而促进CD8 + T细胞募集至微环境。最后,我们显示在用次甲基化剂治疗的乳腺癌患者中MHC-1基因上调。因此,次甲基化剂的免疫调节作用可能涉及上调I类抗原呈递,从而增强CD8 + T细胞反应。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。
更新日期:2018-01-16
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