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 tumor-infiltrating 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. 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 tumor-associated 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 and pathways. Increased IL-6 expression was associated with activation of JAK2/duanyu18133/c-MYC and with decreased PTPRO expression through the axis. Monocytes and TAMs showed significantly increased miR-25-3 p expression, which could target the 3' untranslated region of PTPRO. The miR-25-3 p expression positively correlated with serum IL-6 levels, but inversely correlated with PTPRO in HCC monocytes. activation enhanced in vitro miR-25-3 p transcription and decreased PTPRO, while further promoting PD-L1 secretion. Adoptive cell transfer of c-MYC/miR-25-3 p-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 duanyu18133/c-MYC/miR-25-3 p and by further enhancing PD-L1 expression through JAK2/duanyu18131 and JAK2/duanyu18133/c-MYC signaling.

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