Role of pattern recognition receptors and microbiome-derived growth promoting signals in tumor-immune cell interaction in PDAC

模式识别受体和微生物组衍生的生长促进信号在 PDAC 肿瘤-免疫细胞相互作用中的作用

• 批准号: 391498046
• 负责人: Professor Dr. Stefan Bauer
• 金额: --
• 依托单位: Institut für Immunologie
• 依托单位国家: 德国
• 项目类别: Clinical Research Units
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/391498046?language=en
• 关键词: Role; pattern; recognition; receptors; microbiome

Pattern recognition receptors (PRRs), which include the toll-like receptors (TLRs), play central roles in the innate immune system. They are highly expressed in tumor-associated macrophages (TAMs), but interestingly also in tumor cells themselves. Focusing on the role of TLR7 in the first funding period, we demonstrated that TLR7 promotes tumor cell growth in vitro, while global TLR7 knockout in KPC and KC mouse models did not alter overall tumor growth, probably due to opposing effects in the epithelial and stromal compartments of the tumor microenvironment. Moreover, we generated preliminary data demonstrating tumor-promoting effects of microbiome-derived factors which may be mediated via PRR stimulation. In the second funding period, we therefore plan to i) analyze the potential of different PRRs to mediate tumor cell growth in response to stimulation with endogenous ligands and/or microbiome-derived factors in vitro; ii) characterize the influence of microbiome-derived factors on the interaction between tumor cells and TAMs in vitro; iii) analyze the role of PRRs in mediating growth-stimulatory effects of gut microbiome-derived signals in gnotobiotic mouse models in vivo; and iv) continue identification and characterization of endogenous PRR ligands that promote PRR-mediated tumor progression.

模式识别受体（PRR），包括Toll样受体（TLR），在先天免疫系统中发挥核心作用。它们在肿瘤相关巨噬细胞（TAM）中高度表达，但有趣的是，它们也在肿瘤细胞本身中表达。聚焦于TLR 7在第一个资助期的作用，我们证明了TLR 7在体外促进肿瘤细胞生长，而KPC和KC小鼠模型中的整体TLR 7敲除并没有改变整体肿瘤生长，这可能是由于肿瘤微环境的上皮和基质区室中的相反作用。此外，我们生成了初步数据，表明微生物组衍生因子的促肿瘤作用可能通过PRR刺激介导。因此，在第二个资助期内，我们计划i）分析不同PRR在体外介导肿瘤细胞生长以响应内源性配体和/或微生物组衍生因子刺激的潜力; ii）表征微生物组衍生因子对体外肿瘤细胞与TAM之间相互作用的影响; iii）分析PRR在体内介导肠道微生物组来源的信号在无菌小鼠模型中的生长刺激作用中的作用;和iv）继续鉴定和表征促进PRR介导的肿瘤进展的内源性PRR配体。