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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.

背景

我们之前发现肿瘤浸润 T 细胞中蛋白酪氨酸磷酸酶受体 O（PTPRO）表达降低与免疫抑制有关。本研究旨在探讨人肝癌（HCC）外周单核细胞和肿瘤浸润巨噬细胞中 PTPRO 减少与程序性死亡配体 1（PD-L1）增加之间的关系。

方法

在人和小鼠 HCC 中探索外周单核细胞和肿瘤浸润巨噬细胞中所有指标的表达和相关性。通过体外和体内研究研究了机械调节规律。

结果

我们发现 HCC 外周单核细胞中 PTPRO 表达显著降低，与 HCC 外周单核细胞和肿瘤相关巨噬细胞（TAMs）中 PD-L1 表达增加相关。单核细胞 PD-L1 和 PTPRO 因此可以作为 HCC 术后患者有价值的预后指标，并与 T 细胞耗竭（Tim3+T 细胞）增加相关。PTPRO 耗竭通过 JAK2/STAT1 和 JAK2/STAT3/c-MYC 途径促进单核细胞和巨噬细胞中 PD-L1 的分泌。IL-6 表达增加与 JAK2/STAT3/c-MYC 的激活以及通过 STAT3/c-MYC/miR-25-3p 轴降低 PTPRO 表达有关。单核细胞和 TAMs 显示出明显增加的 miR-25-3p 表达，可靶向 PTPRO 的 3'非翻译区。miR-25-3p 表达与 HCC 单核细胞中的血清 IL-6 水平呈正相关，与 PTPRO 呈负相关。IL-6/STAT3/c-MYC 激活增强了体外 miR-25-3p 转录并降低了 PTPRO，同时进一步促进了 PD-L1 的分泌。c-MYC/miR-25-3p 修饰的单核细胞的过继细胞转移通过下调 PTPRO 并在原位肿瘤移植模型中引起 PD-L1 诱导的免疫抑制，促进肿瘤生长。