IL-6 Promotes PD-L1 Expression In Monocytes And Macrophages By Decreasing Protein Tyrosine Phosphatase Receptor Type O Expression In Human Hepatocellular Carcinoma

Background: We have previously discovered a relationship between the low expression of protein tyrosine phosphatase,receptor type O(PTPRO)in tumorinfiltrating T cells and immunosuppression.The aim of the present study was to investigate the relationship between decreased PTPRO and increased programmed death ligand 1(PD-L1)in both the peripheral monocytes and tumor-infiltrating macrophages of human hepatocellular carcinoma(HCC).Methods: The expression and correlation of all the indices were explored in monocytes and tumor infiltrating macrophages within both human and mice HCC.Using Percoll gradient centrifugation,isolated Tumor-associated Macrophage(TAMs)and Peripheral Blood Mononuclear cyte(PBMC).Western Blot,RT-PCR and flow cytometry were used to detect the expression levels of PTPRO and PD-L1.Western Blot,immunofluorescence co-localization,co-IP and luciferase reporter gene were used to detect the potential mechanism of PTPRO in regulating the expression of PD-L1.The mechanic regulations were studied by using both in vitro and in vivo studies.Results: We found a significant decrease in PTPRO in HCC peripheral monocytes that was associated with increased PD-L1 expression in peripheral monocytes and tumorassociated macrophages(TAMs)in HCC.Monocyte PD-L1 and PTPRO therefore could serve as valuable prognostic indicators for post-surgery patients with HCC and were associated with increased T cell exhaustion(Tim3+ T cells).A depletion of PTPRO promoted PD-L1 secretion in both monocytes and macrophages through the JAK2/STAT1 and JAK2/STAT3/c-MYC pathways.Increased IL-6 expression was associated with activation of JAK2/STAT3/c-MYC and with decreased PTPRO expression through the STAT3/c-MYC/mi R-25-3p axis.Monocytes and TAMs showed significantly increased mi R-25-3p expression,which could target the 3' untranslated region of PTPRO.The mi R-25-3p expression positively correlated with serum IL-6levels,but inversely correlated with PTPRO in HCC monocytes.IL-6/STAT3/c-MYC activation enhanced in vitro mi R-25-3p transcription and decreased PTPRO,while further promoting PD-L1 secretion.Adoptive cell transfer of c-MYC/mi R-25-3p–modified monocytes promoted tumor growth by downregulating PTPRO and causing a PD-L1–induced immunosuppression in an orthotopic tumor transplantation model.Conclusions: Increased serum IL-6 downregulated PTPRO expression in HCC monocytes and macrophages by activating STAT3/c-MYC/mi R-25-3p and by further enhancing PD-L1 expression through JAK2/STAT1 and JAK2/STAT3/c-MYC signaling.