CACNA2D1/PD-L1信号通路调控肺癌干细胞与浸润淋巴细胞相互作用的分子机制

The interaction between cancer stem cell (CSC) and the microenvironmental tumor infiltrating lymphocytes (TIL) and the effect on the malignant properties of tumor cells that play an important role in the development of tumor, and the novel strategy of inhibition this relation has application prospect. However, how the mutual effect between CSC and TIL appears and what is molecular mechanism are on the early stage. Based on the screening of lung CSC markers, our previous study found that CACNA2D1-calcium ion channel subunit and PD-L1 positive populations have CSC properties, and negative relation was shown between CACNA2D1/ PD-L1 and CD8-TIL. Base on our previous data, this project wants to study how CACNA2D1/ PD-L1 influence malignant characteristics of lung cancer cells and influence CSC properties. Furthermore, we want to study the therapeutic effect and the immune response of CACNA2D1/ PD-L1 blockers for the lung cancer transplanted humanized mice. Our project will find the novel regulated mechanism for relation between CSC of lung cancer and TIL and might be provide potential targeted therapy for the new antitumor drug.

肿瘤干细胞（CSC）与肿瘤微环境浸润淋巴细胞（tumor infiltrating lymphocytes，TIL）的相互作用及对于肿瘤细胞恶性特征的影响是肿瘤发生、发展的关键，抑制其交互作用被认为是具有应用前景的抗肿瘤新策略。然而肺癌CSC与TIL之间通过怎样的机制相互影响而改变肿瘤细胞恶性特征的研究仍处于起步阶段。我们前期通过筛选肺癌干细胞分子标志物，发现钙离子通道亚基CACNA2D1以及免疫抑制因子PD-L1阳性细胞亚群具有干细胞特征，并与TIL存在负相关性。本项目将在前期研究基础上，系统研究CACNA2D1/PD-L1与TIL相互作用对于肺癌细胞恶性特征的调控机制。进而研究CACNA2D1/ PD-L1抑制剂对于人源化小鼠肺癌的靶向治疗效果和免疫反应，深入探索参与其相互作用的分子调控机制。本课题将发现新的肺癌CSC与TIL交互作用的全新调控机理，为设计新型抗肿瘤药物提供潜在靶点。

肿瘤细胞具有群体异质性，其中部分细胞具有自我更新功能, 促进肿瘤细胞恶性特征，驱动肿瘤生长等干细胞特性，称之为肿瘤干细胞。肿瘤干细胞与肿瘤复发、转移密切相关，能够抵抗化疗、放疗和靶向治疗。然而，非小细胞肺癌（non-small cell lung cell，NSCLC）仍然缺乏可靠而具有功能性的细胞表面分子标记物识别肿瘤干细胞。因而，在NSCLC细胞系和临床标本中，我们发现电压门控钙通道CACNA2D1（α2δ1）亚基能够特异性识别肿瘤干细胞亚群。α2δ1阳性NSCLC细胞具有自我更新和形成异质性肿瘤等干性特征。α2δ1阳性NSCLC细胞比CD133或CD166阳性细胞更具有干性特征，对于常规化疗不敏感。进而，α2δ1通过介导钙离子内流，激活NFATC2-NOTCH3/ABCG2信号而促进干性特性。此外，α2δ1与PD-L1在靶向耐药的肿瘤细胞中高表达，其高表达与NSCLC患者预后差相关。α2δ1与PD-L1呈正相关，与CD8呈负相关趋势，PD-L1与CD8呈负相关。重要的是，α2δ1特异性抗体通过清除NSCLC移植瘤小鼠的肿瘤干细胞，具有显著的治疗效果。靶向α2δ1信号为抑制肿瘤干细胞而治疗肿瘤提供了潜在临床价值。