Lack of p53 Augments Antitumor Functions in Cytolytic T Cells.
Lack of p53 Augments Antitumor Functions in Cytolytic T Cells.
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DOI：
10.1158/0008-5472.can-15-1798
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发表时间：
2016-09-15
期刊：
影响因子：
11.2
通讯作者：
Mehrotra S
中科院分区：
文献类型：
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作者：
Banerjee A;Thyagarajan K;Chatterjee S;Chakraborty P;Kesarwani P;Soloshchenko M;Al-Hommrani M;Andrijauskaite K;Moxley K;Janakiraman H;Scheffel MJ;Helke K;Armenson K;Palanisamy V;Rubinstein MP;Mayer EG;Cole DJ;Paulos CM;Christina-Voelkel-Johnson;Nishimura MI;Mehrotra S
用同源抗原重复刺激T细胞受体（TCR）导致T细胞的稳健增殖和扩增，并且还用复制性衰老特征标记它们。我们以前的研究表明，T细胞的寿命和抗肿瘤功能可以通过抑制活性氧（ROS）或干预ROS依赖性JNK激活，导致其激活诱导的细胞死亡（AICD）来增强。由于肿瘤抑制蛋白p53也是一种氧化还原活性转录因子，调节细胞ROS的产生，触发下游因子介导的凋亡，我们确定了p53水平是否可以影响肿瘤反应性T细胞的持久性和功能。使用h3 T TCR转基因小鼠，在p53敲除（KO）背景下产生人酪氨酸酶表位反应性T细胞，我们确定其在调节抗肿瘤T细胞功能中的作用。我们的数据显示，与h3 T细胞相比，h3 T-p53 KO T细胞表现出增强的糖酵解定型，其与增加的增殖、IFN-γ分泌、细胞溶解能力、干性基因签名的表达和降低的TGF-β信号传导相关。这种增加的效应子功能与过继转移p53-KO T细胞后皮下建立的鼠黑素瘤的改善的控制相关。使用p53抑制剂的组合对人TCR转导的T细胞的药理学抑制也增强了T细胞效应子功能并改善了持久性。因此，我们的数据突出了p53在调节肿瘤反应性T细胞应答中的关键作用，并且靶向该途径可能在过继性T细胞治疗中具有潜在的翻译意义。
Repetitive stimulation of T cell receptor (TCR) with cognate antigen results in robust proliferation and expansion of the T cells, and also imprints them with replicative senescence signatures. Our previous studies have shown that life-span and anti-tumor function of T cells can be enhanced by inhibiting reactive oxygen species (ROS) or intervening with ROS dependent JNK activation that leads to its activation induced cell death (AICD). Since tumor suppressor protein p53 is also a redox active transcription factor that regulates cellular ROS generation that triggers downstream factor mediating apoptosis, we determined if p53 levels could influence persistence and function of tumor reactive T cells. Using h3T TCR transgenic mice, with human tyrosinase epitope reactive T cells developed on p53 knock-out (KO) background, we determined its role in regulating anti-tumor T cell function. Our data shows that as compared to h3T cells, h3T-p53 KO T cells exhibited enhanced glycolytic commitment that correlated with increased proliferation, IFN-γ secretion, cytolytic capacity, expression of stemness gene signature and decreased TGF-β signaling. This increased effector function correlated to the improved control of subcutaneously established murine melanoma after adoptive transfer of p53-KO T cells. Pharmacological inhibition of human TCR transduced T cells using a combination of p53 inhibitors also potentiated the T cell effector function and improved persistence. Thus, our data highlights the key role of p53 in regulating the tumor reactive T cell response and that targeting this pathway could have potential translational significance in adoptive T cell therapy.