肺泡II型细胞免疫调节功能在慢性炎症相关肺癌发生中的意义

Induction of immune-suppressive microenvironment by chronic inflammation plays a critical role in the development of lung cancer. The key cellular or molecular mechanism of the development of inflammation-associated immune suppressive microenvironment is still unclear. Recently, we found that phenotypic alterations of alveolar type II (AT-II) cells were induced associated with increased Treg infiltration in lung chronic inflammatory environment. Interestingly, AT-II cells from lung chronic inflammatory tissues could induce Treg differentiation, and trigger immature dendritic cell to differentiate toward to regulatory dendritic cell （DCreg）. Thus, we postulate that chronic inflammation may cause AT-II cell to function as a negatively regulatory cell, inducing Treg and DCreg, to inhibit antitumor immunity. In this project, we plan to explore immune function of AT-II cell from urethane-induced chronic lung inflammatory mice model in regulating Treg and DCreg differentiation. Furthermore, we will explore the role of TNF-a/NF-κB signaling pathway in regulating the immune function of AT-II cell in chronic lung inflammatory environment. Finally, we will employ Cre/loxP system (AT-II cell-SP-C promoter driving IκBα mutant) to conditionally disrupt the NF-κB pathway in AT-II cells. In the urethane-treated mice model, we will explore the contribution of immune function of AT-II cell to the development of lung cancer. Understanding the immune function of AT-II cells in the immune suppressive microenvironment may provide a potential drug target for lung cancer immunotherapy

慢性炎症诱导免疫抑制微环境形成在肺癌发生中起重要作用，但介导其形成的关键细胞或分子有待深入研究。我们最近发现慢性炎症诱导肺泡II型上皮细胞(AT-II)表型改变与Treg浸润密切相关；慢性炎症中AT-II诱导Treg分化、诱导DC出现DCreg的表型改变。因此，我们提出假设：慢性炎症可能诱导AT-II发挥免疫抑制作用，在肺免疫抑制微环境形成中起核心作用，促进肺癌发生。本研究拟采用乌拉坦诱导的慢性炎症介导肺癌模型，在慢性炎症期，探讨AT-II是否诱导Treg和DCreg分化而发挥免疫抑制作用,以及炎症中TNF-a/NF-κB通路对AT-II免疫功能的调控作用。应用Cre/loxP构建AT-II细胞NF-κB条件性抑制小鼠，给予乌拉坦诱导肺癌发生，探讨从炎症到肿瘤形成中，AT-II对肺免疫抑制微环境形成以及肺癌发生的影响。揭示AT-II免疫调节作用机制，为肺癌免疫生物学治疗提供新的靶细胞和思路

慢性炎症诱导免疫抑制微环境形成在肺癌发生中起重要作用，但其中关键细胞或分子有待深入研究。我们在申请书中提出假设：慢性炎症诱导AT-II发挥免疫抑制作用而参与肺腺癌的发生。我们发现肺腺癌细胞来源于II型肺泡上皮细胞（Alveolar type II cells）AT-II细胞，并通过高表达MHC-II而发挥免疫抑制作用，进而诱导Treg分化和扩增；我们收集的人肺腺癌组织，发现人肺腺癌细胞主要来源于AT-II，并高表达MHC-II分子，其与肺腺癌组织微环境中FoxP3阳性Treg浸润具有正相关关系。给与TNF-α阻断剂可以抑制炎症诱导的肺腺癌发生，AT-II来源的肺腺癌细胞MHC-II表达明显降低，其诱导CD4 T向Treg分化能力明显减弱。在肿瘤发生前的肺组织炎症反应期，TNF-α依赖的慢性炎症反应通过CXCR-2而上调AT-II细胞MHC-II，进而诱导CD4 T细胞向Treg分化。乌拉坦诱导的炎症介导的肺腺癌发生中，树突状细胞（CD11c+DC）向DCreg转化。给予TNF-α阻断剂抑制炎症介导的肺腺癌发生，其肺组织CD11c+DC的表型分子改变得到逆转，其诱导CD4T向Treg分化的作用受到抑制。TNF-α依赖的肺组织炎症反应诱导AT-II发挥免疫抑制作用，诱导骨髓来源DC表型改变，进而诱导CD4T向Treg分化。另外, 在我们前期发现黄曲霉毒素G1（Aflatoxin G1, AFG1）诱导肺组织炎症反应介导肺腺癌发生、肿瘤细胞来源于AT-II基础上，我们发现整体水平经口给予AFG1诱导TNF-α依赖的小鼠肺组织炎症反应，促进AFG1诱导的AT-II发生氧化DNA损伤。我们还在AFG1诱导实验动物肺腺癌组织中发现，癌细胞高表达炎症细胞因子TNF-α, 提示AFG1诱导肺腺癌炎症微环境形成，TNF-α通过激活NF-kB途径上调抗氧化损伤蛋白SOD-2促进肿瘤细胞EMT。