E.muris菌经由regDC细胞PD-L1介导肺癌免疫监视的机制研究

Although a crucial role of certain types of infections in supporting tumor development by maintaining the pro-tumorigenic microenvironment is well proven (infection-related cancer), the phenomenon of independent development of cancer and infection in the same host, i.e., comorbid cancer-infection progression, has not been studied. New studies are needed to elucidate fundamental principles regulating the effector functions of immune cells in the tumor environment during systemic bacterial infection and identify host and microbial molecules/pathways that can be targeted for treatment or prevention of cancer progression. We have developed an immunocompetent murine model of infection-cancer comorbidity where mice bearing lung cancer are infected with Ehrlichia muris, Gram negative intracellular bacteria. Our preliminary results found that Ehrlichia infection enhanced anti-tumor immunity, inhibited tumor growth and prolonged survival of comorbid mice compared to uninfected tumor-bearing animals. Also, we found that E.muris infection enhancing the antitumor activity was via downregulation accumulation of PD-L1 expression on regDC cells, and subsequently suppression of Treg activation. Based on our previously results, in this study , we will aim to investigate cellular and molecular mechanism to clarify cancer immunesurveillance and immunoediting in a tumor-bearing host with systemic bacterial infections. For this purpose, we will use modern cellular and immunologic technology, proteomic profile array to elucidate E. muris-induced down-regulation of myeloid regulatory cells and alteration of effector and regulatory T cells ,cytokine profile,angiogenesis in tumor microvironment in vitro and vivo. Especially to clarify the molecular mechanism for E.muris-mediated immune activation in PD-L1/PD-1 signaling pathway. This proposal will allow us to translate our finding of the anti-tumor activity of E. muris infection into the mechanism-based clinical application.

感染有助于促进肿瘤发展的微环境，从而支持肿瘤发生。但是感染和癌症在同一宿主中独立发生的现象尚未得到研究，也就是所谓的"感染-癌症共生"模式。探讨此模式介导免疫调节的机制是一个全新的课题。申请人在前期工作中选择E.muris菌的感染作为平台探讨感染-肿瘤共生模式对于肿瘤细胞免疫微环境的调控，证实E.muris菌感染荷瘤鼠延长了生存，其机制是E.muris菌下调regDC细胞表面PD-L1的表达，降低其活性并抑制Treg细胞激活，从而逆转肺癌的免疫逃逸。本项目拟在此基础上，通过体内和体外两条途径，应用细胞生物学、现代免疫学、蛋白组学等, 解析髓系调节细胞，T细胞亚群和肿瘤新生血管的变化表达谱，并以PD-L1/PD-1信号通路为核心阐明E.muris菌介导的抗肿瘤免疫的分子机制。阐述E.muris菌感染如何通过保护性的免疫细胞表达偏倚而产生抗肿瘤免疫效应。为潜在、新颖的免疫治疗模式奠定理论基础。

感染有助于促进肿瘤发展的微环境，从而支持肿瘤发生。但是感染和癌症在同一宿主中独立发生的现象尚未得到研究，也就是所谓的"感染-癌症共生"模式。探讨此模式介导免疫调节的机制是一个全新的课题。原计划E.muris菌作用于机体免疫系统的机制研究，由于E.muris菌生物安全级别高，对实验人员资格培训要求较高，历时较长，本课题组运用具有与E.muris菌相同感染途径及嗜肺性等特点但生物安全等级较低的结核杆菌进行实验，在结核感染-肿瘤共生模式下，探讨了结核分枝杆菌介导的抗肿瘤免疫反应。本项目通过四年的研究工作，研究发现：1）对结核感染-肿瘤共生模式下，肿瘤微环境免疫细胞亚群表达情况的总体分析；2）发现结核分枝杆菌可下调抗原递呈细胞的功能，同时通过激活PD-1/PD-L1信号通路，抑制T细胞免疫应答，从而加强免疫逃逸，促进肿瘤的生长和转移；3）结核杆菌感染荷瘤小鼠，通过激活AKT-mTORC1信号通路上调巨噬细胞PD-L1的表达，促进调节性T细胞（Treg）的分化和其免疫抑制功能，增强免疫逃逸。本研究阐述了结核杆菌感染下肺癌免疫反应的分子机制，促进了对肺癌免疫微环境的深入了解，为进一步的肺癌患者的精准治疗以及联合治疗提供新的视角，为潜在、新颖的免疫治疗模式奠定理论基础。