Low dose decitabine treatment induces CD80 expression in cancer cells and stimulates tumor specific cytotoxic T lymphocyte responses.
Low dose decitabine treatment induces CD80 expression in cancer cells and stimulates tumor specific cytotoxic T lymphocyte responses.
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低剂量地西他滨治疗诱导癌细胞中 CD80 表达并刺激肿瘤特异性细胞毒性 T 淋巴细胞反应
DOI：
10.1371/journal.pone.0062924
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Yu L
中科院分区：
文献类型：
--
作者：
Wang LX;Mei ZY;Zhou JH;Yao YS;Li YH;Xu YH;Li JX;Gao XN;Zhou MH;Jiang MM;Gao L;Ding Y;Lu XC;Shi JL;Luo XF;Wang J;Wang LL;Qu C;Bai XF;Yu L
癌细胞缺乏免疫原性一直被认为是其无法诱导肿瘤特异性T细胞反应的一个主要原因。在本文中，我们提供的证据表明，地西他滨（DAC），一种目前用于治疗骨髓增生异常综合征（MDS）、急性髓系白血病（AML）和其他恶性肿瘤的DNA甲基化抑制剂，能够在小鼠EL4肿瘤模型中引发抗肿瘤细胞毒性T淋巴细胞（CTL）反应。对已形成EL4肿瘤的C57BL/6小鼠，每日用DAC（1.0mg/kg体重）治疗一次，持续5天。我们发现DAC治疗导致产生干扰素 - γ的T淋巴细胞浸润到肿瘤中，并引起肿瘤排斥。清除CD8 + T细胞（而非CD4 + T细胞）会使肿瘤重新生长。DAC诱导的CTL反应似乎是由肿瘤细胞上CD80表达的诱导所引发。表观遗传学证据表明，DAC通过使CD80基因启动子中的CpG二核苷酸位点去甲基化，诱导EL4细胞中CD80的表达。此外，我们还表明，短暂的低剂量DAC治疗能够诱导多种人类癌细胞中CD80基因的表达。这项研究首次提供证据表明，表观遗传调控能够诱导癌细胞上一种主要的T细胞共刺激分子的表达，从而克服免疫耐受，并诱导有效的抗肿瘤CTL反应。这些结果在设计基于DAC的癌症免疫疗法方面具有重要意义。
Lack of immunogenicity of cancer cells has been considered a major reason for their failure in induction of a tumor specific T cell response. In this paper, we present evidence that decitabine (DAC), a DNA methylation inhibitor that is currently used for the treatment of myelodysplastic syndrome (MDS), acute myeloid leukemia (AML) and other malignant neoplasms, is capable of eliciting an anti-tumor cytotoxic T lymphocyte (CTL) response in mouse EL4 tumor model. C57BL/6 mice with established EL4 tumors were treated with DAC (1.0 mg/kg body weight) once daily for 5 days. We found that DAC treatment resulted in infiltration of IFN-γ producing T lymphocytes into tumors and caused tumor rejection. Depletion of CD8+, but not CD4+ T cells resumed tumor growth. DAC-induced CTL response appeared to be elicited by the induction of CD80 expression on tumor cells. Epigenetic evidence suggests that DAC induces CD80 expression in EL4 cells via demethylation of CpG dinucleotide sites in the promoter of CD80 gene. In addition, we also showed that a transient, low-dose DAC treatment can induce CD80 gene expression in a variety of human cancer cells. This study provides the first evidence that epigenetic modulation can induce the expression of a major T cell co-stimulatory molecule on cancer cells, which can overcome immune tolerance, and induce an efficient anti-tumor CTL response. The results have important implications in designing DAC-based cancer immunotherapy.
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影响因子：
11.5
作者：
Fonsatti, Ester;Nicolay, Hugues J. M.;Maio, Michele
通讯作者：
Maio, Michele
影响因子：
3.9
作者：
Coral, S;Sigalotti, L;Maio, M
通讯作者：
Maio, M
影响因子：
6.4
作者：
Serrano, A;Tanzarella, S;Garrido, F
通讯作者：
Garrido, F
影响因子：
64.5
作者：
CHEN, LP;ASHE, S;LINSLEY, PS
通讯作者：
LINSLEY, PS
影响因子：
20.3
作者：
Oki, Yasuhiro;Jelinek, Jaroslav;Issa, Jean-Pierre J.
通讯作者：
Issa, Jean-Pierre J.