Gut microbiome directs hepatocytes to recruit MDSC and promote cholangiocarcinoma

• Published in: Cancer discovery Vol. 11; no. 5; pp. 1248 - 1267
• Main Authors: Zhang, Qianfei, Ma, Chi, Duan, Yi, Heinrich, Bernd, Rosato, Umberto, Diggs, Laurence P., Ma, Lichun, Roy, Soumen, Fu, Qiong, Brown, Zachary J., Wabitsch, Simon, Thovarai, Vishal, Fu, Jianyang, Feng, Dechun, Ruf, Benjamin, Cui, Linda L., Subramanyam, Varun, Frank, Karen M., Wang, Sophie, Kleiner, David E., Ritz, Thomas, Rupp, Christian, Gao, Bin, Longerich, Thomas, Kroemer, Alexander, Wang, Xin Wei, Ruchirawat, Mathuros, Korangy, Firouzeh, Schnabl, Bernd, Trinchieri, Giorgio, Greten, Tim F.
• Format: Journal Article
• Language: English
• Published: 15.12.2020
• ISSN: 2159-8274; 2159-8290
• DOI: 10.1158/2159-8290.CD-20-0304

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 suppressor cells (PMN-MDSC). 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 even in the absence of liver disease or colitis. Our study demonstrates that the gut microbiome controls hepatocytes to form an immunosuppressive environment by increasing PMN-MDSC to promote liver cancer.