CBM 信号复合体调控ILC3功能参与结肠肿瘤发生的分子机制

Environmental difference and particularly alimentary customs, which probably affect the commensal microbita, are responsible for the geographical variation in colorectal cancer incidence. Although, the vast majority of studies on commensal microbiota have focused on gut bacteria, recent studies have begun to note the importance of commensal fungi in gut. A rich fungal community that interacts with the immune system was proved in mammalian gut. However, how commensal fungi interacts with immune system and whether this interaction affects colonic tumor development remains unknown. .In our preliminary studies, we found that both CARD9 and MALT1 deficient mice had higher tumor burdens than wide type mice. The number of tumors was decreased after treatment of fluconazole. We also found that the level of ILC3 and production of IL22 was increased in Malt1 knockout mice. Meanwhile, CARD9 knockout mice were both more susceptible to DSS-induced colitis than wild type mice. Based on our preliminary studies, we propose to characterize the molecular mechanism by which CBM signalsome leads to altered immunity to commensal fungi in the gut; to determine how CBM signalsome regulate the function of ILC3 and therefore influence colorectal cancer. .Together, these lines of investigation will reveal molecular mechanism by which host innate immune system affect colonic epithelial homeostasis in response to commensal fungal dysbiosis, which will provide the molecular basis of potential therapeutic targets for designing adjuvant and vaccine against microbial dysbiosis in gut.

肠道特异性免疫在肠炎癌发生发展中起关键作用，其形成的根本原因是肠道局域免疫细胞对肠道不同菌群及其代谢产物的反应。CARD9-BCL10-MALT1（CBM）信号复合体作为MAPK等炎症信号通路的上游信号，是启动机体对病原菌免疫应答的关键通路。然而，迄今尚不清楚该信号复合体介导抗病原菌免疫应答在肠道肿瘤恶性进程中的作用。我们前期建立了炎症相关结肠肿瘤模型，发现CARD9-/-鼠和MALT1-/-鼠结肠肿瘤较野生鼠加重，而予氟康唑抗真菌治疗能显著缓解肿瘤，特别是MALT1-/-鼠结肠固有层中3型固有淋巴细胞（ILC3）变化极为显著。推测肠道真菌可能通过CBM信号复合体调控ILC3功能，参与结肠肿瘤的发生。本课题拟通过分析结肠肿瘤发生发展中CBM信号复合体调控肠道局域免疫的作用，探讨CBM信号复合体调控ILC3分化和功能的分子机制，为揭示肠道局域免疫影响临床控制结肠肿瘤的免疫治疗提供新理论。

已有较多研究证实肠道细菌参与结直肠癌的发生发展，但关于肠道共生真菌介导的免疫应答是否影响结肠肿瘤的发生尚无报道。本项目研究发现C型凝集素受体Dectin-3敲除后，Dectin-3-/-鼠比野生鼠易患炎症相关结肠肿瘤。值得关注的是Dectin-3-/-鼠肠道中真菌的数量，尤其是条件致病真菌白色念珠菌（C. albicans）的数量显著高于正常鼠；Dectin-3-/-鼠在肠道肿瘤诱导过程中予白色念珠菌灌胃可显著加重炎性病变及肿瘤负荷，而给予氟康唑抗真菌治疗后，Dectin-3-/-结肠肿瘤负荷显著减轻，提示我们在Dectin-3-/-中增多的肠道真菌促进了结肠肿瘤的进程。进一步研究发现在Dectin-3-/-结肠肿瘤鼠中IL22的水平显著增高，并鉴定出固有淋巴细胞3（ILC3）是IL22的主要来源。IL-22的单克隆抗体或者anti-CD90去除ILC3细胞后均能显著抑制白色念珠菌诱导的促癌作用。进一步的机制研究发现，白色念珠菌诱导巨噬细胞糖酵解，促进巨噬细胞分泌IL-7。增多的IL-7可以与IL23协同，促进ILC3细胞分泌IL22。该研究证实了Dectin-3及其下游CBM复合物介导的抗真菌免疫应答在维持肠道稳态和诱导肠道肿瘤中的重要作用，阐述了肠道共生真菌在结肠肿瘤发病中机制，对于临床结肠肿瘤的诊治具有重要的指导意义。