DNA demethylating agent decitabine broadens the peripheral T cell receptor repertoire.
DNA demethylating agent decitabine broadens the peripheral T cell receptor repertoire.
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DNA 去甲基化剂地西他滨拓宽了外周 T 细胞受体库
DOI：
10.18632/oncotarget.9352
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发表时间：
2016-06-21
期刊：
影响因子：
--
通讯作者：
Han W
中科院分区：
文献类型：
--
作者：
Nie J;Zhang Y;Li X;Chen M;Liu C;Han W
目的地西他滨是一种很有前途的表观免疫抑制剂，在实体瘤患者中已显示出临床疗效，但其抗肿瘤机制尚不清楚。我们的目的是研究地西他滨对外周血T细胞的免疫调节作用。实验设计我们应用新一代测序技术研究TCRβ基因的互补决定区3（complementary-determining region 3，CDR 3），其多样性是宿主免疫系统识别通用外源抗原的先决条件。我们收集了4例患者的外周血单个核细胞（PBMC），在基线和2个周期的低剂量地西他滨治疗后。结果4例患者经地西他滨治疗后，TCRβ CDR 3的特异性序列均增加，表现为扩增克隆丰度降低，TCR多样性增加。进一步的分析显示，CD 4 T细胞对地西他滨治疗的响应具有增加的CD 4/CD 8比率的趋势。此外，全基因组表达的改变证实了地西他滨对免疫重建的影响，并验证了TCR切除环（TRECs）的增加。结论低剂量DNMT抑制剂地西他滨可拓宽外周血T细胞库，为表观遗传修饰剂在抗肿瘤免疫增强中提供了新的作用。
Purpose Decitabine, a promising epi-immunotherapeutic agent has shown clinical responses in solid tumor patients, while the anti-tumor mechanisms were unclear. We aimed to investigate the immunomodulatory effect of decitabine in peripheral T cells. Experimental design We applied next-generation sequencing to investigate the complementarity-determining region 3 (CDR3) of the TCRβ gene, the diversity of which acts as the prerequisite for the host immune system to recognize the universal foreign antigens. We collected the peripheral blood mononuclear cells (PBMCs) from 4 patients, at baseline and after 2 cycles of low-dose decitabine therapy. Results An increase of the unique productive sequences of the CDR3 of TCRβ was observed in all of the 4 patients after decitabine treatment, which was characterized by a lower abundance of expanded clones and increased TCR diversity compared with before decitabine treatment. Further analysis showed a tendency for CD4 T cells with an increased CD4/CD8 ratio in response to decitabine therapy. In addition, the genome-wide expression alterations confirmed the effects of decitabine on immune reconstitution, and the increase of TCR excision circles (TRECs) was validated. Conclusions The low-dose DNMT inhibitor decitabine broadens the peripheral T cell repertoire, providing a novel role for the epigenetic modifying agent in anti-tumor immune enhancement.
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影响因子：
56.9
作者：
Arstila, TP;Casrouge, A;Kourilsky, P
通讯作者：
Kourilsky, P
DOI：
10.1158/1078-0432.ccr-13-2648
发表时间：
2014-05-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Robert L;Tsoi J;Wang X;Emerson R;Homet B;Chodon T;Mok S;Huang RR;Cochran AJ;Comin-Anduix B;Koya RC;Graeber TG;Robins H;Ribas A
通讯作者：
Ribas A
影响因子：
29.4
作者：
Gehring, Adam J.;Ho, Zi Zong;Bertoletti, Antonio
通讯作者：
Bertoletti, Antonio
影响因子：
56.9
作者：
Messaoudi, I;Guevara-Patiño, JA;Nikolich-Zugich, J
通讯作者：
Nikolich-Zugich, J
影响因子：
7
作者：
Freeman, J. Douglas;Warren, Rene L.;Holt, Robert A.
通讯作者：
Holt, Robert A.