Abstract P048: Steatosis promote liver cancer development by inducing chemokine production from Kupffer cells
Authors: Stiles Bangyan L. , Tu Taojian , He Lina , Alba Mario 
Published: January 2022

Liver cancer is hallmarked with chronic inflammation resulting from underlying liver diseases such as liver steatosis. Steatotic liver injury recruits inflammatory cells and establishes the tumor immune environment that can promote the development of liver cancer. Previously, we showed that macrophages produce growth factors to promote liver cancer growth in a genetic model where steatosis and liver tumors were induced by the deletion of tumor suppressor Pten (phosphatase and tensin homologue deleted on chromosome 10). In this model, we showed that attenuating steatosis and depletion of macrophages leads to inhibition of liver cancer development. To investigate the recruitment and functions of immune cells in liver cancer, we analyzed the expression profiles of these tumors as well as tumors from other mouse models together with human liver samples. Our analysis of the inflammatory cytokines identified one chemokine that was commonly upregulated in all tumor model and attenuated in non-tumor models. CXCL5 is a member of the neutrophil-activating chemokines. In the Pten deleted liver tumors, CXCL5 is significantly upregulated whereas its expression is inhibited when steatosis is attenuated via caloric restriction or deletion of a metabolic kinase, Akt2. We explored the cell types that may produce CXCL5. To our surprise, the upregulation of CXCL5 is concurrent with increases in macrophage but not neutrophil populations. We further observed significant upregulation of CXCL5 mRNA expression in Kupffer cells, the liver resident macrophages isolated from the Pten deleted mice. We explored the hypothesis that macrophages secrets CXCL5 to establish the tumor environment and promote tumor growth. Our data showed that CXCL5 treatment increased mouse hepatocytes and human HepG2 cells proliferation. This effect is blocked by inhibition of CXCR2, the receptor for CXCL5. Additionally, we explored the mechanisms of CXCL5 upregulation in Kupffer cells and discovered that lipopolysaccharide (LPS) induces the expression of CXCL5 by nearly 20-fold in Kupffer cells. This is in contrast with the lack of induction in murine macrophage cell lines and primary peritoneal macrophages. This unique response of Kupffer cells suggests that the source of CXCL5 in the Pten deletion mouse model is likely Kupffer cells. This data is collaborated by bioinformatic analysis of datasets where steatotic liver injury is induced by diet feeding. Furthermore, analysis of patient proteomic data detected CXCL5 as the primary chemokine that is induced in tumors among other neutrophil-activating peptides. In summary, our data identified CXCL5 as a novel chemokine produced by Kupffer cells that plays key roles in steatosis driven liver cancer development. Chronic liver diseases such as steatohepatitis can establish tumorigenesis environment through accumulation of LPS stimulated CXCL5 release from Kupffer cells.

Citation Format: Bangyan L. Stiles, Taojian Tu, Lina He, Mario Alba. Steatosis promote liver cancer development by inducing chemokine production from Kupffer cells [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2021 Oct 5-6. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(1 Suppl):Abstract nr P048.