Epigenetic priming restores the HLA class-I antigen processing machinery expression in Merkel cell carcinoma.
Epigenetic priming restores the HLA class-I antigen processing machinery expression in Merkel cell carcinoma.
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DOI：
10.1038/s41598-017-02608-0
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发表时间：
2017-05-23
影响因子：
4.6
通讯作者：
Becker JC
中科院分区：
文献类型：
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作者：
Ritter C;Fan K;Paschen A;Reker Hardrup S;Ferrone S;Nghiem P;Ugurel S;Schrama D;Becker JC
默克尔细胞癌 (MCC) 是一种罕见且具有侵袭性但具有高度免疫原性的皮肤癌。后者是由于其病毒或紫外线相关的致癌作用。对于肿瘤进展，MCC 必须逃避宿主的免疫监视，例如由于 HLA I 类表达丧失。事实上，在 MCC 肿瘤组织和 MCC 细胞系中观察到 HLA I 类表达降低。 HLA I 类表面表达减少是由抗原加工机制 (APM) 关键组件（包括 LMP2 和 LMP7 以及 TAP1 和 TAP2）表达受损引起的。值得注意的是，HLA-I 类结合肽的实验规定恢复了 MCC 细胞上的 HLA-I 类表面表达。 HLA I 类 APM 的沉默是由于组蛋白脱乙酰化所致，因为组蛋白脱乙酰酶 (HDAC) 的抑制不仅诱导相应启动子区域中组蛋白的乙酰化，而且还诱导 APM 成分的重新表达。因此，HDAC 抑制可在体外和小鼠异种移植模型中恢复 HLA I 类表面表达。与干扰素重新诱导 HLA I 类相反，HDAC 抑制剂不会干扰免疫优势病毒蛋白的表达。总之，通过表观遗传启动恢复 MCC 细胞上的 HLA I 类表达是增强适应性免疫反应的治疗的一种有吸引力的方法。
Merkel cell carcinoma (MCC) is a rare and aggressive, yet highly immunogenic skin cancer. The latter is due to its viral or UV-associated carcinogenesis. For tumor progression MCC has to escape the host’s immuno-surveillance, e.g. by loss of HLA class-I expression. Indeed, a reduced HLA class-I expression was observed in MCC tumor tissues and MCC cell lines. This reduced HLA class-I surface expression is caused by an impaired expression of key components of the antigen processing machinery (APM), including LMP2 and LMP7 as well as TAP1 and TAP2. Notably, experimental provisions of HLA class-I binding peptides restored HLA class-I surface expression on MCC cells. Silencing of the HLA class-I APM is due to histone deacetylation as inhibition of histone deacetylases (HDACs) not only induced acetylation of histones in the respective promoter regions but also re-expression of APM components. Thus, HDAC inhibition restored HLA class-I surface expression in vitro and in a mouse xenotransplantation model. In contrast to re-induction of HLA class-I by interferons, HDAC inhibitors did not interfere with the expression of immuno-dominant viral proteins. In summary, restoration of HLA class-I expression on MCC cells by epigenetic priming is an attractive approach to enhance therapies boosting adaptive immune responses.