SLC7A2 Deficiency Promotes Hepatocellular Carcinoma Progression By Recruiting Of Myeloid-derived Suppressors Cells

Background&Aims:Hepatocellular carcinoma(HCC)is the third leading cause of cancerrelated deaths worldwide.It is highly aggressive and the incidence is increasing year by year.However,there is no effective treatment strategies.Myeloid-derived suppressor cells(MDSCs)in tumor microenvironment are heterogeneous immature immunosuppressive myeloid cell populations,which mainly enhance tumor progression by suppressing the function of T cells.However,the cause and molecular mechanism of MDSCs recruitment induced by HCC oncogenic signal remain unclear.SLC7A2 inhibits the accumulation of macrophages and alleviates the development of colon cancer associated with colitis.Whereas,the role of SLC7A2 in HCC is not well understood.Therefore,this study aims to investigate the mechanism of SLC7A2 and MDSCs in HCC tumor immune evasion,and provide new targets and strategies for HCC metastasis and treatment.Methods:TCGA and GEO databases,qRT-PCR,Western blot and tissue microarray were used to analyze SLC7A2 expression in HCC.Chemokine and receptor PCR microarray were used to verify the expression level of chemokine induced by SLC7A2 in HCC.Further in vitro and in vivo methods including qRT-PCR,Western blot,ELISA,immunohistochemistry,immunofluorescence of cells and tissues,in vivo imaging of small animals and animal experiments were used to detect the effect of SLC7A2 on HCC metastasis and its regulatory molecular mechanism.In addition,MDSCs migration and immune-cytometry were used to detect MDSCs recruitment and intra-tumoral immune cell infiltration.Results:This study reported the role of SLC7A2 in mediating HCC invasion and metastasis,and found that SLC7A2 was down-regulated in HCC tissues and HCC cells.The expression of SLC7A2 was significantly negatively correlated with clinical metastasis and poor prognosis of HCC patients.Up-regulation of SLC7A2 inhibited the growth and metastasis of HCC,while down-regulation of SLC7A2 promoted the growth and metastasis of HCC.This study further found that low expression of SLC7A2 in HCC,promoted HCC growth and metastasis by mediating tumor immune evasion.The lack of SLC7A2 expression in HCC,CXCL1 level and secretion were mainly reinforced via the PI3K/AKT/NF-κB pathway,and then MDSCs were recruited through the CXCL1-CXCR2 axis to enhance the invasion and metastasis of HCC.In addition,the elimination of MDSCs with anti-Gr-1 antibody or the recruitment inhibition of MDSCs with CXCR2 inhibitor SB265610 significantly restricted HCC growth and metastasis.Conclusions:The SLC7A2 low expression was an independent risk factor for survival and prognosis of patients with HCC.The down-regulated of SLC7A2 in HCC recruited MDSCs through CXCL1,which maintained the tumor suppressive microenvironment and induced tumor immune escape to boost HCC growth and metastasis.Based on chemokines and MDSCs in tumor microenvironment,this study expanded the mechanism of HCC invasion and metastasis,and provided a new perspective for tumor immune mechanism and immunotherapy of HCC.