Increased IFNγ+ T Cells Are Responsible for the Clinical Responses of Low-Dose DNA-Demethylating Agent Decitabine Antitumor Therapy
Increased IFNγ+ T Cells Are Responsible for the Clinical Responses of Low-Dose DNA-Demethylating Agent Decitabine Antitumor Therapy
复制标题
增加的 IFN gamma( ) T 细胞是低剂量 DNA 去甲基化剂地西他滨抗肿瘤治疗临床反应的原因
DOI：
10.1158/1078-0432.ccr-17-1201
复制
发表时间：
2017-10-15
影响因子：
11.5
通讯作者：
Han, Weidong
中科院分区：
文献类型：
--
作者：
Li, Xiang;Zhang, Yan;Han, Weidong
目的：低剂量DNA去甲基化剂地西他滨治疗癌症患者是有效的。生物标志物预测治疗反应和潜在的抗肿瘤机制，特别是对宿主抗肿瘤免疫的影响在很大程度上仍然难以捉摸。实验设计：在体外和体内检测低剂量地西他滨对T细胞的影响。此外，还涉及了接受低剂量地西他滨治疗的晚期实体瘤患者的测试队列和验证队列。流式细胞仪和CCK-8法检测CD 3（+）T细胞的活化、增殖、极化和细胞溶解能力。进行KaplanMeier和考克斯比例风险回归分析以研究地西他滨表观遗传治疗后增强的T细胞活性的预后价值。低剂量地西他滨治疗增强人IFN γ（+）T细胞的活化和增殖，促进Th 1极化和细胞毒性T细胞的活性，从而抑制癌症进展并增强患者的临床效果。在临床试验中，增加IFN γ T+细胞和增加T细胞的细胞毒性预测改善的治疗反应和生存在测试cohort和validationcohort.Conclusions：我们发现，低剂量的地西他滨治疗促进抗肿瘤T细胞反应，通过促进T细胞增殖和增加IFN γ（+）T细胞可能作为一个潜在的预后生物标志物的地西他滨为基础的抗肿瘤治疗的反应。（C）2017年AACR。
Purpose: Low-dose DNA-demethylating agent decitabine therapy is effective in a subgroup of cancer patients. It remains largely elusive for the biomarker to predict therapeutic response and the underlying antitumor mechanisms, especially the impact on host antitumor immunity. ExperimentalDesign: The influence of low-dose decitabine on T cells was detected both in vitro and in vivo. Moreover, a test cohort and a validation cohort of advanced solid tumor patients with low-dose decitabine-based treatment were involved. The activation, proliferation, polarization, and cytolysis capacity of CD3(+)T cells were analyzed by FACS and CCK8 assay. KaplanMeier and Cox proportional hazard regression analysis were performed to investigate the prognostic value of enhanced T-cell activity following decitabine epigenetic therapy.Results: Low-dose decitabine therapy enhanced the activation and proliferation of human IFN gamma(+) T cells, promoted Th1 polarization and activity of cytotoxic T cells both in vivo and in vitro, which in turn inhibited cancer progression and augmented the clinical effects of patients. In clinical trials, increased IFN gamma T+ cells and increased T-cell cytotoxicity predicted improved therapeutic responses and survival in the test cohort and validation cohort.Conclusions: We find that low-dose decitabine therapy promotes antitumor T-cell responses by promoting T-cell proliferation and the increased IFN gamma(+) T cells may act as a potential prognostic biomarker for the response to decitabine- based antitumor therapy. (C)2017 AACR.