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Midkine inhibition enhances anti-PD-1 immunotherapy in sorafenib-treated hepatocellular carcinoma via preventing immunosuppressive MDSCs infiltration 期刊论文

编号：

A4A90BB660D76E431561228109181211
作者：

Ding, Lijuan(丁丽娟)#^[1]Wang, Nanya(王楠娅)^[2]Wang, Qiang(王强)^[1]Fan, Xia^[1];Xin, Yuning^[1];Wang, Shudong(王树东)*^[3]
语种：

英文
期刊：

CELL DEATH DISCOVERY ISSN：2058-7716 2023 年 9 卷 1 期 ; MAR 11
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摘要：

Sorafenib, a multiple-target tyrosine kinase inhibitor, is the standard of care for patients with advanced hepatocellular carcinoma (HCC), but provides limited benefits. Emerging evidences suggest that prolonged sorafenib treatment induces an immunosuppressive HCC microenvironment, but the underling mechanism is undetermined. In the present study, the potential function of midkine, a heparin-binding growth factor/cytokine, was evaluated in sorafenib-treated HCC tumors. Infiltrating immune cells of orthotopic HCC tumors were measured by flow cytometry. Differentially expressed genes in sorafenib-treated HCC tumors were evaluated by transcriptome RNA sequencing. The potential function of midkine were evaluated by western blot, T cell suppression assay, immunohistochemistry (IHC) staining and tumor xenograft model. We found that sorafenib treatment increased intratumoral hypoxia and altered HCC microenvironment towards an immune-resistant state in orthotopic HCC tumors. Sorafenib treatment promoted midkine expression and secretion by HCC cells. Moreover, forced midkine expression stimulated immunosuppressive myeloid-derived suppressor cells (MDSCs) accumulation in HCC microenvironment, while knockdown of midkine exhibited opposite effects. Furthermore, midkine overexpression promoted CD11b(+)CD33(+)HLA-DR- MDSCs expansion from human PBMCs, while midkine depletion suppressed this effect. PD-1 blockade showed no obvious inhibition on tumor growth of sorafenib-treated HCC tumors, but the inhibitory effect was greatly enhanced by midkine knockdown. Besides, midkine overexpression promoted multiple pathways activation and IL-10 production by MDSCs. Our data elucidated a novel role of midkine in the immunosuppressive microenvironment of sorafenib-treated HCC tumors. Mikdine might be a potential target for the combination of anti-PD-1 immunotherapy in HCC patients.
推荐引用方式
GB/T 7714：

Ding Lijuan,Wang Nanya,Wang Qiang, et al. Midkine inhibition enhances anti-PD-1 immunotherapy in sorafenib-treated hepatocellular carcinoma via preventing immunosuppressive MDSCs infiltration [J].CELL DEATH DISCOVERY,2023,9(1).
APA：

Ding Lijuan,Wang Nanya,Wang Qiang,Fan Xia,&Wang Shudong.(2023).Midkine inhibition enhances anti-PD-1 immunotherapy in sorafenib-treated hepatocellular carcinoma via preventing immunosuppressive MDSCs infiltration .CELL DEATH DISCOVERY,9(1).
MLA：

Ding Lijuan, et al. "Midkine inhibition enhances anti-PD-1 immunotherapy in sorafenib-treated hepatocellular carcinoma via preventing immunosuppressive MDSCs infiltration" .CELL DEATH DISCOVERY 9,1(2023).
入库时间：

4/1/2023 10:40:35 PM
更新时间：

4/1/2023 10:40:35 PM
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