Neutrophil-independent Roles of CXCL5 in Hepatocellular Carcinoma Chronic inflammation is a hallmark of hepatocellular carcinoma (HCC) development, however not all immune cells are increased in the liver tumor. In fact, a recent analysis of human HCC showed that while macrophages are enriched in the tumors compared to healthy livers, most cytotoxic immune cells (including neutrophils) are decreased in the tumors. Macrophages quantity also negatively correlated with HCC patient survival rate. To investigate the recruitment and functions of immune cells in HCC, we collected human HCC samples and multiple different HCC mouse models including our liver-specific PTEN deletion model, their chemokine expression profile were analyzed. The only chemokine that was significantly upregulated in all samples was CXCL5, a member of the neutrophil-activating chemokines. Examination of liver immune cell population in wild-type mice with no tumors and liver-specific PTEN deletion mice bearing liver tumors showed that Kupffer cells, but not neutrophils, significantly increased in tumorous livers. We believe that increased Kupffer cells contributed to the CXCL5 increase during HCC. We saw a significant upregulation of Kupffer cells CXCL5 mRNA expression in HCC-bearing mice compared to healthy mice. We are the first to report that murine CXCL5 is over-expressed by Kupffer cells in response to LPS which is commonly accumulated in chronic liver diseases across different etiologies (alcoholic, HCV, HBV, NAFLD). We believe that this is a unique function of Kupffer cells, because our data and previous studies showed that murine macrophage cell lines and primary peritoneal macrophages do not produce CXCL5 in response to LPS. Additionally, CXCL5 treatment increased mouse hepatocytes proliferation in a dose dependent manner, this effect is blocked by CXCR2 inhibition. Analysis of TCGA database showed that high CXCL5 expression significantly decreased human HCC patient survival. Together, these data revealed a novel role of CXCL5 in HCC, where chronic liver diseases provides tumorigenesis environment through accumulation of LPS, its stimulation on Kupffer cells results in over-expression of CXCL5 which promotes HCC tumor cells proliferation.