苯并芘诱发的肺慢性炎症中免疫抑制微环境促进肺癌的发生发展

The sustained existence of chronic lung inflammation is a major driving force for the development of lung cancer. B[a]P and its metabolite B[a]PDE are the most important complete carcinogens that are responsible for both chronic lung inflammation and lung cancer. However, the molecular mechanisms to trigger and maintain chronic lung inflammation and thus lead to lung cancer especially in the context of an immunosuppressive microenvironment following B[a]P exposure have not yet been explored. Our recent studies showed that the sustained induction of TNFα was indispensable for the formation and maintenance of B[a]P-induced chronic lung inflammation and lung cancer development, and that B[a]P/B[a]PDE not only directly transformed bronchial epithelial cells to develop precancerous/cancerous lesions, but also led to the formation of an immunosuppressive microenvironment such as enhanced accumulation and immunosuppressive functions of myeloid-derived suppressor cells (MDSC), exhaustion of CD4/CD8 effector T cells, T regulatory cell(Treg) expansion, NK cell dysfunction and increasing conversion from M1 to M2 of polarized alveolar macrophages in chronic inflammatory lung tissue. Therefore, we are going to test and verify the following molecular mechanisms: through the sustained induction of TNFα, B[a]P promoted enhanced accumulation and immunosuppressive functions of MDSCs in chronic inflammatory lung tissue, further leading to exhaustion of CD4/CD8 effector T cells, T regulatory cell (Treg) expansion, NK cell dysfunction and increasing conversion from M1 to M2 of polarized alveolar macrophages, which finally developed into lung cancer. At the same time we are planning to perform the immunotherapy against TNFα or/and PD-1 at the early and middle stages of B[a]P-induced chronic lung inflammation to overcome the immunosuppressive microenvironment in chronic inflammatory lung tissue in order to prevent or retard the lung cancer development.

我们新近研究表明：TNFα表达持续上调对B[a]P诱导的肺慢性炎症微环境的形成与维持、以及肺癌的发生发展不可或缺；B[a]P除直接作用于支气管上皮细胞导致其发生癌前病变/癌变外，还可促使肺慢性炎症组织内MDSC募集增加及其免疫抑制功能增强、CD4/CD8 T细胞耗竭、Treg细胞扩增、NK细胞功能障碍、巨噬细胞由M1型至M2型的极化作用增强等免疫抑制微环境的形成。因此，本研究拟进一步验证“B[a]P通过TNFα表达持续上调促使肺慢性炎症组织内MDSC募集增加及其免疫抑制功能增强、进而促进免疫抑制微环境的形成(包括CD4/CD8 T细胞耗竭、Treg细胞扩增、NK细胞功能障碍、巨噬细胞由M1型至M2型的极化作用增强等)，最终导致肺癌发生发展”的分子机制，并在肺慢性炎症的早/中期针对TNFα或/和PD-1进行免疫治疗研究，以便通过改善肺慢性炎症组织内免疫抑制微环境以防止或延缓肺癌的发生发展。

我们研究表明：TNFα表达持续上调对B[a]P诱导的肺慢性炎症微环境的形成与维持、以及肺癌的发生发展不可或缺；B[a]P除直接作用于支气管上皮细胞导致其发生癌前病变/癌变外，还可促使肺慢性炎症组织内MDSC募集增加及其免疫抑制功能增强、CD4/CD8 T细胞耗竭、Treg细胞扩增、NK细胞功能障碍、巨噬细胞由M1型至M2型的极化作用增强等免疫抑制微环境的形成。因此，本研究初步验证了如下假说：“B[a]P通过TNFα表达持续上调促使肺慢性炎症组织内MDSC募集增加及其免疫抑制功能增强、进而促进免疫抑制微环境的形成(包括CD4/CD8 T细胞耗竭、Treg细胞扩增、NK细胞功能障碍、巨噬细胞由M1型至M2型的极化作用增强等)，最终导致肺癌发生发展”，并初步证实了在肺慢性炎症的早/中期针对TNFα或/和PD-1进行免疫治疗研究，可通过改善肺慢性炎症组织内免疫抑制微环境以防止或延缓肺癌的发生发展。