免疫检查点对于实现免疫反应的精准控制具有关键作用，近年来发现免疫检查点阻断剂可以明显增加T淋巴细胞对肿瘤的识别，但是此类阻断剂在大多数肺癌患者体内最终未能形成持久的反应而出现病情进展。研究发现阻断剂失效可能是肿瘤浸润性T淋巴细胞（TILs）表观调控功能耗竭的结果。然而，目前仍缺乏系统深入对肺癌TILs表观调控机制的研究。我们提出假说：肺癌TILs表观调控的改变，可引起T淋巴细胞功能耗竭，导致免疫逃逸，而发现关键的调控靶点，将对肺癌早期精准诊断及干预有着重要的意义。为此，我们拟采用ATAC-Seq测序技术，分析肺癌浸润CD8+T淋巴细胞表观调控特征，寻找引起肺癌浸润CD8+T淋巴细胞功能耗竭表观调控靶点；在体外培养T淋巴细胞，采用CRISPR-cas9技术敲除靶点基因，寻找CD8+T淋巴细胞染色质状态，转录因子结合位点及信号通路的改变，研究TILs表观调控功能耗竭导致肺癌发生发展的作用机制。

Immune checkpoints play a key role in precise control of the immune response. In recent years, immune checkpoint inhibitors were found to significantly increase the recognition of T lymphocytes. However, such inhibitors fail to form a lasting response in most lung cancer patients and appear to progress. It was found that the failure of checkpoint inhibitors may be the result of exhaustion of tumor infiltrating T lymphocytes (TILs). However, there was still lack of comprehensive research on the epigenetic regulation mechanism of TILs. Based on recent advances and our previous research results, we propose the hypothesis: the epigenetic regulation of TILs in lung cancer could cause the exhaustion of T lymphocytes, which leads to be ineffective of inhibitors, so find the key epigenetic targets will be significant to the precise diagnosis and intervention of lung cancer. Therefore, we intend to base on ATAC-Seq technology, and analyze the relationship between the epigenetic regulatory characteristics of infiltrating CD8+T lymphocytes and tumor escape, and find out the epigenetic targets for the exhaustion of the infiltrating CD8+T lymphocytes. Then we would culture T lymphocytes in vitro, and take CRISPR-cas9 technology to knock down target genes, so as to observe changes in chromatin states, transcription factor binding sites and signaling pathways of CD8+ T lymphocytes. Finally we would study the exhaustion mechanism of TILs epigenetic regulation comprehensively.