Analysis of cancer-related immune suppressor mechanisms in mice

肠道菌群失调常见于肝硬变和慢性胃肠道疾病患者，但其对肝脏抗肿瘤免疫功能的影响尚不清楚。在这里，我们研究了肠道微生物群如何影响胆管癌细胞的抗肿瘤免疫。原发性硬化性胆管炎(PSC)或结肠炎是两种已知的胆管癌危险因素，它们促进了小鼠肿瘤的发展，导致CXCR2+髓系衍生免疫抑制细胞(PMN-MDSC)在肝脏中积聚。在PSC和结肠炎小鼠中观察到的肠道屏障功能的下降使肠道来源的细菌和脂多糖(LPS)出现在肝脏中，并通过TLR4依赖的机制和CXCR2+PMN-MDSC的积聚诱导肝细胞表达CXCL1。相反，即使在没有肝脏疾病和/或结肠炎的情况下，新霉素治疗也能阻止CXCL1的表达，PMN-MDSC的积聚，并抑制肝脏肿瘤的生长。粪便移植研究表明，与健康对照组相比，来自肝硬变患者的粪便样本诱导了无菌小鼠肝脏PMN-MDSC的积聚。我们的研究表明，肠道微生物通过增加PMN-MDSC来控制肝细胞形成免疫抑制环境，从而促进肝癌的发生。

Gut dysbiosis is commonly observed in patients with cirrhosis and chronic gastrointestinal disorders, however, its effect on anti-tumor immunity in the liver is largely unknown. Here we studied how the gut microbiome affects anti-tumor immunity in cholangiocarcinoma. Primary sclerosing cholangitis (PSC) or colitis, two known risk factors for cholangiocarcinoma, which promote tumor development in mice caused an accumulation of CXCR2+ polymorphonuclear myeloid-derived immunosuppressive cells (PMN-MDSC) in the liver. A decrease in gut barrier function observed in mice with PSC and colitis allowed gut derived bacteria and lipopolysaccharide (LPS) to appear in the liver and induced CXCL1 expression in hepatocytes through a TLR4-dependent mechanism and an accumulation of CXCR2+ PMN-MDSC. On the contrary, neomycin treatment blocked CXCL1 expression, PMN-MDSC accumulation and inhibited tumor growth in the liver even in the absence of liver disease and or colitis. Fecal transplant studies demonstrated that fecal samples derived from patients with cirrhosis induced hepatic PMN-MDSC accumulation in germ free mice compared to healthy controls. Our study demonstrates that the gut microbiome controls hepatocytes to form an immunosuppressive environment by increasing PMN-MDSC to promote liver cancer.