Andreev Katerina, Trufa Denis Iulian, Siegemund Raphaela, Rieker Ralf, Hartmann Arndt, Schmidt Joachim, Sirbu Horia, Finotto Susetta
Department of Molecular Pneumology, Friedrich-Alexander-University of Erlangen-Nürnberg, Erlangen 91054, Germany.
Department of Thoracic Surgery, Friedrich-Alexander-University of Erlangen-Nürnberg, Erlangen 91054, Germany.
Br J Cancer. 2015 Sep 15;113(6):902-13. doi: 10.1038/bjc.2015.255. Epub 2015 Sep 8.
In spite of modern therapies for non-small-cell lung cancer (NSCLC), prognosis for many patients is still poor and survival rates are low. Immunotherapy is the possibility to improve the lung immune response surrounding the tumour. However, this approach requires detailed understanding of the local immune-responses of NSCLC patients.
We analysed samples from three different regions within the lungs of NSCLC patients, whereas we distinguished between patients suffering from adenocarcinoma and squamous cell carcinoma. Expression of type 1 T helper (Th1)/type 1 cytotoxic (Tc1) factors was assessed by quantitative real-time PCR, western blot analyses or immunohistochemistry. Cytotoxic cell activity of CD8(+) T cells was determined via co-culture with autologous tumour cells and apoptosis assay.
We found decreased levels of the transcription factor T-box expressed in T cells (T-bet or Tbx21) and of the downstream activated IFN-γ-dependent pSTAT1α isoform in the lung tumour areas of patients with NSCLC as compared with tumour-free control regions. In these patients, reduced T-bet and pSTAT1α levels were found associated with increased immunosuppressive markers like cytotoxic T lymphocyte-associated protein 4, programmed cell death 1 and with a suppression of the Th1 cell cytokine production and Tc1 cell activity.
These findings confirm a central role of T-bet in targeted immunotherapy for patients with NSCLC.
尽管有针对非小细胞肺癌（NSCLC）的现代治疗方法，但许多患者的预后仍然很差，生存率较低。免疫疗法有可能改善肿瘤周围的肺部免疫反应。然而，这种方法需要详细了解NSCLC患者的局部免疫反应。
我们分析了NSCLC患者肺部三个不同区域的样本，同时区分了腺癌和鳞状细胞癌患者。通过定量实时PCR、蛋白质印迹分析或免疫组织化学评估1型辅助性T细胞（Th1）/1型细胞毒性T细胞（Tc1）因子的表达。通过与自体肿瘤细胞共培养和凋亡检测来确定CD8(+) T细胞的细胞毒性活性。
我们发现，与无肿瘤对照区域相比，NSCLC患者肺部肿瘤区域中T细胞表达的转录因子T盒（T-bet或Tbx21）以及下游活化的IFN-γ依赖性pSTAT1α异构体水平降低。在这些患者中，发现T-bet和pSTAT1α水平降低与细胞毒性T淋巴细胞相关蛋白4、程序性细胞死亡蛋白1等免疫抑制标志物增加以及Th1细胞细胞因子产生和Tc1细胞活性的抑制有关。
这些发现证实了T-bet在NSCLC患者靶向免疫治疗中的核心作用。
