Immune suppressor mechanisms in patients with GI cancer

Division Of Basic Sciences - Nci

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Abstract

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.