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

模式识别受体(PRRs)包括Toll样受体(TLRs)，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。着眼于TLR7在第一个资助期的作用，我们证明了TLR7在体外促进了肿瘤细胞的生长，而在KPC和KC小鼠模型中全局敲除TLR7并没有改变整个肿瘤的生长，可能是由于肿瘤微环境中上皮和间质的相反作用。此外，我们产生了初步的数据，证明了微生物组衍生因子的肿瘤促进作用，可能是通过PRR刺激介导的。因此，在第二个资助期，我们计划：i)分析不同的PRRs在体外对内源性配体和/或微生物衍生因子刺激介导肿瘤细胞生长的潜在作用；ii)表征微生物衍生因子对肿瘤细胞与TAMs体外相互作用的影响；iii)在体内分析PrRs在介导肠道微生物衍生信号的促生长效应中的作用；以及iv)继续鉴定和鉴定促进PRR介导的肿瘤进展的内源性PRR配体。

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.