Dual anti-OX40/IL-2 therapy augments tumor immunotherapy via IL-2R-mediated regulation of OX40 expression.
Dual anti-OX40/IL-2 therapy augments tumor immunotherapy via IL-2R-mediated regulation of OX40 expression.
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DOI：
10.1371/journal.pone.0034467
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Weinberg AD
中科院分区：
文献类型：
--
作者：
Redmond WL;Triplett T;Floyd K;Weinberg AD
通过TNFR超家族成员，包括OX 40（CD 134）和4-1BB（CD 137）提供T细胞共刺激，提供了促进T细胞存活和分化的关键信号。最近的研究表明，OX 40的连接可以在临床前模型中增强T细胞介导的抗肿瘤免疫，更重要的是，OX 40激动剂正在临床开发用于癌症免疫治疗。OX 40作为治疗靶点特别令人感兴趣，因为它不在幼稚T细胞上表达，而是在TCR刺激后瞬时上调。虽然TCR参与是诱导OX 40表达所必需的，但调节OX 40本身的下游信号仍不清楚。在这项研究中，我们证明，OX 40的表达是通过TCR和共同的γ链酪氨酸依赖性信号级联反应，需要JAK 3介导的下游转录因子STAT 3和STAT 5的激活进行调节。此外，用激动剂抗0X 40 mAb和IL-2的组合治疗增强了针对多种肿瘤类型的肿瘤免疫疗法。双重疗法还能够恢复具有长期良好建立（>5周）肿瘤的小鼠中的无反应性肿瘤反应性CD 8 T细胞的功能，从而导致荷瘤宿主的存活增加。总之，这些数据揭示了TCR/共同γ链细胞因子信号传导调节0X 40表达的能力，并证明了通过提供双重抗0X 40/共同γ链精氨酸导向疗法来增强癌症免疫疗法的新手段。
The provision of T cell co-stimulation via members of the TNFR super-family, including OX40 (CD134) and 4-1BB (CD137), provides critical signals that promote T cell survival and differentiation. Recent studies have demonstrated that ligation of OX40 can augment T cell-mediated anti-tumor immunity in pre-clinical models and more importantly, OX40 agonists are under clinical development for cancer immunotherapy. OX40 is of particular interest as a therapeutic target as it is not expressed on naïve T cells but rather, is transiently up-regulated following TCR stimulation. Although TCR engagement is necessary for inducing OX40 expression, the downstream signals that regulate OX40 itself remain unclear. In this study, we demonstrate that OX40 expression is regulated through a TCR and common gamma chain cytokine-dependent signaling cascade that requires JAK3-mediated activation of the downstream transcription factors STAT3 and STAT5. Furthermore, combined treatment with an agonist anti-OX40 mAb and IL-2 augmented tumor immunotherapy against multiple tumor types. Dual therapy was also able to restore the function of anergic tumor-reactive CD8 T cells in mice with long-term well-established (>5 wks) tumors, leading to increased survival of the tumor-bearing hosts. Together, these data reveal the ability of TCR/common gamma chain cytokine signaling to regulate OX40 expression and demonstrate a novel means of augmenting cancer immunotherapy by providing dual anti-OX40/common gamma chain cytokine-directed therapy.
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新型STAT5靶基因的体内鉴定。
影响因子：
14.9
作者：
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