Van Andel Research Institute (VARI), Grand Rapids, MI, USA.
Princess Margaret Cancer Centre, University Health Network (UHN), Toronto, Ontario, Canada.
Nat Rev Cancer. 2019 Mar;19(3):151-161. doi: 10.1038/s41568-019-0109-9.
DNA methylation inhibitors have become the mainstay for treatment of certain haematological malignancies. In addition to their abilities to reactivate genes, including tumour suppressors, that have acquired DNA methylation during carcinogenesis, they induce the expression of thousands of transposable elements including endogenous retroviruses and latent cancer testis antigens normally silenced by DNA methylation in most somatic cells. This results in a state of viral mimicry in which treated cells mount an innate immune response by turning on viral defence genes and potentially expressing neoantigens. Furthermore, these changes mediated by DNA methylation inhibitors can also alter the function of immune cells relevant to acquired immunity. Additionally, other inhibitors of epigenetic processes, such as histone deacetylases, methylases and demethylases, can elicit similar effects either individually or in combinations with DNA methylation inhibitors. These findings together with rapid development of immunotherapies open new avenues for cancer treatment.
DNA 甲基化抑制剂已成为治疗某些血液恶性肿瘤的主要方法。除了能够重新激活在癌变过程中获得 DNA 甲基化的基因，包括肿瘤抑制基因外，它们还诱导数千种转座元件的表达，包括内源性逆转录病毒和潜伏的睾丸癌抗原，这些基因在大多数体细胞中通常被 DNA 甲基化沉默。这导致了一种类似病毒的状态，其中受治疗的细胞通过开启病毒防御基因并可能表达新抗原来启动先天免疫反应。此外，DNA 甲基化抑制剂介导的这些变化也可以改变与获得性免疫相关的免疫细胞的功能。此外，其他表观遗传过程抑制剂，如组蛋白去乙酰化酶、甲基化酶和去甲基化酶，单独或与 DNA 甲基化抑制剂联合使用，也可以产生类似的效果。这些发现与免疫疗法的快速发展一起为癌症治疗开辟了新的途径。
