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。

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.