Concomitant NAFLD Facilitates Liver Metastases and PD-1-Refractory by Recruiting MDSCs via CXCL5/CXCR2 in Colorectal Cancer

Abstract

Background and AimsBoth Non-alcoholic fatty liver disease (NAFLD) and colorectal cancer (CRC) are prevalent worldwide. The effect of concomitant NAFLD on the risk of colorectal liver metastasis (CRLM) and its mechanisms have not been definitively elucidated. MethodsWe observed the effect of concomitant NAFLD on CRLM in the mouse model, and explored the underlying mechanisms of specific myeloid-derived suppressor cells (MDSCs) recruitment, then tested the therapeutic application based on the mechanisms; finally we validated our findings in the clinical samples. ResultsHere we prove that in different mouse models, NAFLD induces F4/80+ Kupffer cells to secret chemokine CXCL5, then recruits CXCR2+ myeloid-derived suppressor cells (MDSCs) to promote the growth of CRLM. CRLM with NAFLD background are refractory to the anti-PD-1 monoclonal antibody treatment, but when combined with Reparixin, an inhibitor of CXCR1/2, dual-therapy cures the established CRLM in mice with NAFLD. Our clinical studies also indicate that fatty liver diseases increase the infiltration of CXCR2+ MDSCs, as well as the hazard of liver metastases in CRC patients. ConclusionsCollectively, our findings highlight the significance of a selective CXCR2+/CD11b+/Gr-1+ subset myeloid cells in favoring the development of CRLM with NAFLD background, and identify a pharmaceutic medicine which is already available for the clinical trials and potential treatment.