5HT/5HT1aR调控抑郁相关性肺癌保护性自噬通路p62-STAT3诱导免疫抑制的机制研究

During chronic stress the lung cancer patients with depression like behaviors can cause tumor invasion and metastasis, and the final and fatal step in the progression, but the underlying mechanisms remain poorly understood. Depression, a chronic stress factor, can stimulate the secretion of 5-HT, can affect the immune function and promote the growth of tumor. Here 64 human lung cancer patients with major depression and 64 human lung cancer patients individuals were recruited in the study, tumor the level of 5-HT was increased, and the survival time was significantly correlated with the expression of 5-HT1aR. Downregulation of P62, up regulation of BECN1, activation of STAT3 induce B7-H1, B7-H2 and other inhibitory signals resulted in the decrease of specific T cell lysis. However, supposedly“5-HT/5HT1aR is a key factor to induce tumor immune escape, and p62-STAT3 autophagy signaling is an important pathway for the specific T cell killing in the lung cancer patients with depression”. The study intends to using clinical samples, cells of knockdown 5HT1aR with depression for tumor model, from the organization, cell and molecular level to study the molecular mechanisms between 5-HT/5-HT1aR induce tumor immune escape and autophagy induced activation of p62-STAT3 resistance specific T cell killing for the lung cancer patients with depression like behaviors, which provides a new way for the lung cancer patients with depression.

肺癌合并抑郁症的患者在精神压力下导致肿瘤侵袭和转移、加速患者死亡。其确切机制尚未阐明。研究证实, 抑郁刺激5-羟色胺分泌影响机体免疫功能、促进肿瘤生长。本课题组通过128名抑郁相关性肺癌患者及非抑郁肺癌患者分析，发现抑郁相关性肺癌患者5-HT水平增高；生存时间缩短与5HT1R呈负相关。P62下调、BECN1上调、STAT3活化上调B7-H1, B7-H2等抑制性信号导致肿瘤特异性T细胞活性降低。据此推测“5-HT/5HT1aR是抑郁相关性肺癌诱导免疫逃逸的关键因素， p62-STAT3自噬信号是抑郁相关性肺癌抵抗特异性T细胞杀伤的重要通路”。本课题拟利用患者样本、5HT1aR敲除细胞结合抑郁荷瘤模型, 从整体、细胞及分子水平上探讨5-HT/5-HT1aR与抑郁相关性肺癌诱导免疫抑制及激活p62-STAT3自噬抵抗特异性T细胞杀伤的分子机制，为抑郁相关性肺癌患者治疗提供一种新思路。

肺癌患者出现精神抑郁症状的机率大约为20 %-29 % , 长期处于情绪低落、抑郁等精神压力应激状况被诊断为抑郁症的肺癌患者，会降低治疗效果导致患者生存时间显著缩短。5-HT能促发抑郁，也具有免疫调节作用，当5-HT作用于肿瘤细胞表面的5HTRs能增加抗肿瘤的特异性淋巴细胞凋亡，TH1型细胞因子减少，诱导肿瘤细胞发生免疫逃逸及促进肿瘤生长。因此针对5HT/5HTRs为靶点及其诱导的肿瘤免疫逃逸机制可能是抑郁相关性肺癌患者治疗的一个新的方向。.将5-HT1aR作为一个分子作用靶点引入到抑郁相关性肺癌患者发生免疫逃逸研究，通过探讨抑郁相关性肺癌通过5-HT作用于肺癌细胞的5-HT1aR产生免疫逃逸进行研究，深入阐明其诱导STAT3信号通路抵抗CTL细胞的肿瘤特异性免疫细胞杀伤作用机制，并进一步细胞、亚细胞水平上证实抑郁相关性肺癌激活肿瘤保护性自噬通路p62-STAT3的机制是抑郁相关性肺癌诱导免疫逃逸的关键环节。为抑郁相关性肺癌免疫逃逸发生机制提供重要理论依据；同时对5-HT/5-HT1aR和肿瘤保护性自噬通路进行深入研究，对肿瘤防治提供更多的治疗选择，基础理论研究的成果更具有临床实用性。在项目执行期内，研究经费使用合理，除完成既定目标外还充实了研究内容，为所在实验室开创了新的技术平台。研究结果发表2篇SCI（影响因子大于5分）收录论文，尚有2篇SCI文章待发表。