IL-6 promotes PD-L1 expression in monocytes and macrophages by decreasing protein tyrosine phosphatase receptor type O expression in human hepatocellular carcinoma
IL-6 promotes PD-L1 expression in monocytes and macrophages by decreasing protein tyrosine phosphatase receptor type O expression in human hepatocellular carcinoma
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IL-6通过降低人肝细胞癌中O型蛋白酪氨酸磷酸酶受体表达来促进单核细胞和巨噬细胞中PD-L1的表达
DOI：
10.1136/jitc-2019-000285
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发表时间：
2020
影响因子：
10.9
通讯作者：
Jiang Runqiu
中科院分区：
文献类型：
--
作者：
Zhang Wenjie;Liu Yang;Yan Zhongyi;Yang Hui;Sun Wei;Yao Yongliang;Chen Yun;Jiang Runqiu
背景我们先前发现肿瘤浸润性T细胞中蛋白酪氨酸磷酸酶O型受体（PTPRO）的低表达与免疫抑制之间的关系。本研究的目的是探讨人肝细胞癌（HCC）外周血单核细胞和肿瘤浸润巨噬细胞中PTPRO降低和程序性死亡配体1（PD-L1）升高之间的关系。方法检测人和小鼠肝癌组织中单核细胞和肿瘤浸润巨噬细胞中上述指标的表达及相关性。采用离体和体内实验研究了其力学调节作用。结果我们发现肝癌外周血单核细胞中PTPRO的显著降低与肝癌外周血单核细胞和肿瘤相关巨噬细胞（TAM）中PD-L1表达的增加相关。因此，单核细胞PD-L1和PTPRO可作为HCC术后患者有价值的预后指标，并与T细胞耗竭（Tim 3 +T细胞）增加相关。PTPRO的消耗通过JAK 2/STAT 1和JAK 2/STAT 3/c-MYC途径促进单核细胞和巨噬细胞中的PD-L1分泌。IL-6表达的增加与JAK 2/STAT 3/c-MYC的激活以及通过STAT 3/c-MYC/miR-25-3 p轴的PTPRO表达的降低相关。单核细胞和TAM显示miR-25-3 p表达显著增加，其可以靶向PTPRO的3′非翻译区。HCC单核细胞中miR-25-3 p的表达与血清IL-6水平呈正相关，与PTPRO呈负相关。IL-6/STAT 3/c-MYC激活增强体外miR-25-3 p转录并降低PTPRO，同时进一步促进PD-L1分泌。在原位肿瘤移植模型中，c-MYC/miR-25-3 p修饰的单核细胞的连续细胞转移通过下调PTPRO并引起PD-L1诱导的免疫抑制来促进肿瘤生长。结论血清IL-6水平升高通过激活STAT 3/c-MYC/miR-25-3 p下调肝癌单核细胞和巨噬细胞PTPRO表达，并通过JAK 2/STAT 1和JAK 2/STAT 3/c-MYC信号通路进一步增强PD-L1表达。
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 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/miR-25–3 p 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. IL-6/STAT3/c-MYC 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 STAT3/c-MYC/miR-25–3 p and by further enhancing PD-L1 expression through JAK2/STAT1 and JAK2/STAT3/c-MYC signaling.