Banerjee Anirban, Thyagarajan Krishnamurthy, Chatterjee Shilpak, Chakraborty Paramita, Kesarwani Pravin, Soloshchenko Myroslawa, Al-Hommrani Mazen, Andrijauskaite Kristina, Moxley Kelly, Janakiraman Harinarayanan, Scheffel Matthew J, Helke Kristi, Armenson Kent, Palanisamy Viswanathan, Rubinstein Mark P, Mayer Elizabeth-Garrett, Cole David J, Paulos Chrystal M, Nishimura Michael I, Mehrotra Shikhar
Department of Surgery, Medical University of South Carolina, Charleston, SC 29425.
Department of Surgery, Oncology Institute, Loyola University, Maywood, IL 60153.
Cancer Res. 2016 Sep 15;76(18):5229-5240. doi: 10.1158/0008-5472.CAN-15-1798. Epub 2016 Jul 27.
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 antitumor 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. Because 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 knockout (KO) background, we determined its role in regulating antitumor T-cell function. Our data show that as compared with h3T cells, h3T-p53 KO T cells exhibited enhanced glycolytic commitment that correlated with increased proliferation, IFNγ 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 highlight 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. Cancer Res; 76(18); 5229-40. ©2016 AACR.
用同源抗原重复刺激T细胞受体（TCR）会导致T细胞强劲增殖和扩增，同时也会使其带有复制性衰老特征。我们之前的研究表明，通过抑制活性氧（ROS）或干预依赖ROS的JNK激活（其会导致激活诱导的细胞死亡），可以增强T细胞的寿命和抗肿瘤功能。由于肿瘤抑制蛋白p53也是一种氧化还原活性转录因子，可调节触发下游因子介导凋亡的细胞ROS生成，因此我们确定p53水平是否会影响肿瘤反应性T细胞的持久性和功能。利用h3T TCR转基因小鼠，其在p53基因敲除（KO）背景下产生了对人酪氨酸酶表位有反应的T细胞，我们确定了p53在调节抗肿瘤T细胞功能中的作用。我们的数据表明，与h3T细胞相比，h3T-p53 KO T细胞表现出增强的糖酵解倾向，这与增殖增加、IFNγ分泌、细胞溶解能力、干性基因特征表达以及TGF-β信号传导降低相关。这种增强的效应器功能与p53-KO T细胞过继转移后对皮下建立的小鼠黑色素瘤的更好控制相关。使用p53抑制剂组合对人TCR转导的T细胞进行药理学抑制也增强了T细胞效应器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细胞反应中的关键作用，并且靶向该途径在过继性T细胞治疗中可能具有潜在的转化意义。《癌症研究》；76(18)；5229 - 40。©2016美国癌症研究协会。
