Targeting the YB-1/PD-L1 Axis to Enhance Chemotherapy and Antitumor Immunity
Targeting the YB-1/PD-L1 Axis to Enhance Chemotherapy and Antitumor Immunity
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靶向 YB-1/PD-L1 轴增强化疗和抗肿瘤免疫
DOI：
10.1158/2326-6066.cir-18-0648
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发表时间：
2019
影响因子：
10.1
通讯作者：
Chen Ke
中科院分区：
文献类型：
--
作者：
Tao Zhen;Ruan Hailong;Sun Lin;Kuang Dong;Song Yongchun;Wang Qi;Wangs Tao;Hao Yi;Chen Ke
YB-1信号轴促进肿瘤免疫逃避和多药耐药。当靶向时，化疗耐药性降低，抗肿瘤反应增强，这表明了治疗肿瘤多药耐药性和免疫抑制肿瘤微环境的途径。肿瘤细胞在肿瘤化疗耐药中可以逃避免疫破坏，但其机制尚不清楚。Y-box结合蛋白1（YB-1）在化疗耐药肿瘤细胞中上调，在获得多药耐药性中发挥作用。在这里，我们证明化疗诱导肿瘤中的免疫抑制微环境，并通过YB-1介导的程序性死亡-1配体1（PD-L1）上调诱导免疫逃避。YB-1蛋白和mRNA的检测显示，肝细胞癌（HCC）中YB-1表达增加。高YB-1表达与HCC患者的总生存率呈负相关。YB-1表达与PD-L1正相关，并且YB-1通过结合PD-L1启动子基序诱导PD-L1表达。YB-1表达在化学抗性HCC细胞中上调，并且由于PD-L1表达被阻断，YB-1敲低通过肿瘤微环境中的T细胞活化逆转化学抗性。我们还发现，肿瘤免疫抑制环境和免疫逃避的抑制伴随着功能性细胞毒性CD 8 + T细胞的增殖和骨髓源性抑制细胞和调节性T细胞在肿瘤环境中的抑制。我们的数据表明，靶向YB-1信号传导轴，同时逆转肿瘤免疫逃避和多药耐药性，可能会改善抗肿瘤反应。这一发现表明了一种针对肿瘤化疗耐药性的治疗方式。
The YB-1 signaling axis promotes tumor immune evasion and multidrug resistance. When targeted, chemoresistance decreased and antitumor responses were enhanced, suggesting an avenue for treating tumor multidrug resistance and immunosuppressive tumor microenvironments. Tumor cells can escape immune destruction in tumor chemoresistance, but the mechanism for this phenomenon remains unclear. Y-box binding protein 1 (YB-1), which is upregulated in chemoresistant tumor cells, plays a role in the acquisition of multidrug resistance. Here, we demonstrate that chemotherapy induced an immunosuppressive microenvironment in the tumor and induced immune evasion through YB-1–mediated programmed death-1 ligand 1 (PD-L1) upregulation. Examination of the YB-1 protein and mRNA showed an increase in YB-1 expression in hepatocellular carcinoma (HCC). High YB-1 expression negatively correlated with the overall survival of HCC patients. YB-1 expression positively correlated with PD-L1, and YB-1 induced PD-L1 expression by binding a PD-L1 promoter motif. YB-1 expression was upregulated in chemoresistant HCC cells, and YB-1 knockdown reversed chemoresistance via T-cell activation in the tumor microenvironment due to blocked PD-L1 expression. We also found that inhibition of the tumor immunosuppressive environment and immune evasion was accompanied by proliferation of functional cytotoxic CD8+ T cells and inhibition of myeloid-derived suppressor cells and regulatory T cells in the tumor environment. Our data indicate that targeting the YB-1 signaling axis, which simultaneously reverses both tumor immune evasion and multidrug resistance, may improve the antitumor response. This finding suggests a treatment modality against tumor chemoresistance.