Low-Dose Decitabine Augments the Activation and Anti-Tumor Immune Response of IFN-γ(+) CD4(+) T Cells Through Enhancing IκBα Degradation and NF-κB Activation.
Low-Dose Decitabine Augments the Activation and Anti-Tumor Immune Response of IFN-γ(+) CD4(+) T Cells Through Enhancing IκBα Degradation and NF-κB Activation.
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低剂量地西他滨通过增强 I kappa B α 降解和 NF-kappa B 激活来增强 IFN-gamma( ) CD4( ) T 细胞的激活和抗肿瘤免疫反应
DOI：
10.3389/fcell.2021.647713
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发表时间：
2021
影响因子：
5.5
通讯作者：
Nie J
中科院分区：
文献类型：
--
作者：
Li X;Dong L;Liu J;Wang C;Zhang Y;Mei Q;Han W;Xie P;Nie J
γ+T细胞在控制肿瘤生长中起着多重作用，增加干扰素-CD8+T辅助细胞群可促进细胞介导的抗肿瘤免疫应答。我们先前已经证明，小剂量DNA去甲基化药物地西他滨治疗可促进CD3+T细胞的增殖和细胞毒作用；然而，对纯化的CD4+T细胞的直接调节及其潜在机制尚不清楚。体外和体内检测小剂量地西他滨对分选的CD4+T细胞的影响。用流式细胞仪和DELFIA时间分辨荧光检测法分析CD4+T细胞的活化、增殖、细胞内细胞因子的产生和杀伤活性。采用体内泛素化实验检测蛋白质降解情况。此外，还检测了接受地西他滨治疗的实体瘤患者分选的κ+T细胞中的磷酸化p65和I-CD4Bα水平。小剂量地西他滨可促进分选的CD_4~+T细胞的增殖和活化，增加干扰素-γ~+T细胞亚群的比例，增强体内外的细胞杀伤活性。NF-κB抑制剂BAY 11-7082抑制地西他滨诱导的T细胞增殖和干扰素-γ的产生。在机制上，小剂量地西他滨可增强E3连接酶β-TrCP的表达，促进I-κBα的泛素化和降解，并导致核因子-κB的激活。值得注意的是，我们观察到，在体外，低剂量地西他滨治疗诱导了CD4+T细胞中NF-κB的激活，这些患者对地西他滨启动的化疗有反应，而不是那些没有反应的患者。这些数据表明，小剂量地西他滨通过促进I-κBα降解，从而促进核因子-κB的激活和干扰素-γ的产生，从而增强CD_4+T细胞的抗肿瘤免疫。
CD4+ T cells play multiple roles in controlling tumor growth and increasing IFN-γ+ T-helper 1 cell population could promote cell-mediated anti-tumor immune response. We have previously showed that low-dose DNA demethylating agent decitabine therapy promotes CD3+ T-cell proliferation and cytotoxicity; however, direct regulation of purified CD4+ T cells and the underlying mechanisms remain unclear. The effects of low-dose decitabine on sorted CD4+ T cells were detected both in vitro and in vivo. The activation, proliferation, intracellular cytokine production and cytolysis activity of CD4+ T cells were analyzed by FACS and DELFIA time-resolved fluorescence assays. In vivo ubiquitination assay was performed to assess protein degradation. Moreover, phosphor-p65 and IκBα levels were detected in sorted CD4+ T cells from solid tumor patients with decitabine-based therapy. Low-dose decitabine treatment promoted the proliferation and activation of sorted CD4+ T cells, with increased frequency of IFN-γ+ Th1 subset and enhanced cytolytic activity in vitro and in vivo. NF-κB inhibitor, BAY 11-7082, suppressed decitabine-induced CD4+ T cell proliferation and IFN-γ production. In terms of mechanism, low-dose decitabine augmented the expression of E3 ligase β-TrCP, promoted the ubiquitination and degradation of IκBα and resulted in NF-κB activation. Notably, we observed that in vitro low-dose decitabine treatment induced NF-κB activation in CD4+ T cells from patients with a response to decitabine-primed chemotherapy rather than those without a response. These data suggest that low-dose decitabine potentiates CD4+ T cell anti-tumor immunity through enhancing IκBα degradation and therefore NF-κB activation and IFN-γ production.
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影响因子：
7.3
作者：
Takeuchi A;Saito T
通讯作者：
Saito T
影响因子：
8.7
作者：
Shih HY;Sciumè G;Poholek AC;Vahedi G;Hirahara K;Villarino AV;Bonelli M;Bosselut R;Kanno Y;Muljo SA;O'Shea JJ
通讯作者：
O'Shea JJ
从头表观遗传程序抑制PD-1封锁介导的T细胞再生。
影响因子：
64.5
作者：
Ghoneim HE;Fan Y;Moustaki A;Abdelsamed HA;Dash P;Dogra P;Carter R;Awad W;Neale G;Thomas PG;Youngblood B
通讯作者：
Youngblood B
影响因子：
3.8
作者：
Lee, Wei-Chen;Wu, Ting-Jung;Wang, Chao-Ching
通讯作者：
Wang, Chao-Ching
影响因子：
8.7
作者：
Oh H;Ghosh S
通讯作者：
Ghosh S