Multiple Structural and Epigenetic Defects in the Human Leukocyte Antigen Class I Antigen Presentation Pathway in a Recurrent Metastatic Melanoma Following Immunotherapy
Multiple Structural and Epigenetic Defects in the Human Leukocyte Antigen Class I Antigen Presentation Pathway in a Recurrent Metastatic Melanoma Following Immunotherapy
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DOI：
10.1074/jbc.m115.676130
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发表时间：
2015-10-30
影响因子：
4.8
通讯作者：
Ferrone, Soldano
中科院分区：
文献类型：
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作者：
Chang, Chien-Chung;Pirozzi, Giuseppe;Ferrone, Soldano
关于恶性细胞中多个HLA I类抗原加工机制缺陷的分子基础的信息很少，尽管这些信息有助于我们理解肿瘤细胞所利用的分子免疫逃逸机制，并可能提出对抗它们的策略。在本研究中，我们揭示了免疫治疗后复发性黑色素瘤转移的IFN-γ-不可逆结构和HLA I类抗原加工机制中的表观遗传缺陷的组合。这些缺陷包括tapasin和一种HLA单倍型的缺失以及HLA-A3基因对IFN-γ的反应性的选择性沉默。Tapasin丢失是由外显子3中的种系移码突变（TAPBP（684 delA））沿着其他基因拷贝的体细胞丢失引起的。HLA-A3基因及其IFN-γ应答性的选择性沉默与启动子α位点附近的CpG甲基化和TATA盒相关，DNA甲基转移酶1缺失后可逆。这种治疗与tapasin重建和IFN-γ刺激相结合，恢复了最高水平的HLA I类表达及其引发细胞毒性T细胞应答的能力。这些结果代表了一种新的肿瘤免疫逃避机制，通过在HLA I类抗原呈递途径中的不同水平上损害多种组分。这些发现可能表明利用DNA去甲基化和IFN-γ应答的组合癌症免疫疗法的合理设计。
Scant information is available about the molecular basis of multiple HLA class I antigen-processing machinery defects in malignant cells, although this information contributes to our understanding of the molecular immunoescape mechanisms utilized by tumor cells and may suggest strategies to counteract them. In the present study we reveal a combination of IFN-gamma-irreversible structural and epigenetic defects in HLA class I antigen-processing machinery in a recurrent melanoma metastasis after immunotherapy. These defects include loss of tapasin and one HLA haplotype as well as selective silencing of HLA-A3 gene responsiveness to IFN-gamma. Tapasin loss is caused by a germline frameshift mutation in exon 3 (TAPBP(684delA)) along with a somatic loss of the other gene copy. Selective silencing of HLA-A3 gene and its IFN-gamma responsiveness is associated with promoter CpG methylation nearby site-alpha and TATA box, reversible after DNA methyltransferase 1 depletion. This treatment combined with tapasin reconstitution and IFN-gamma stimulation restored the highest level of HLA class I expression and its ability to elicit cytotoxic T cell responses. These results represent a novel tumor immune evasion mechanism through impairing multiple components at various levels in the HLA class I antigen presentation pathway. These findings may suggest a rational design of combinatorial cancer immunotherapy harnessing DNA demethylation and IFN-gamma response.