Checkpoint regulator B7x is epigenetically regulated by HDAC3 and mediates resistance to HDAC inhibitors by reprogramming the tumor immune environment in colorectal cancer
Checkpoint regulator B7x is epigenetically regulated by HDAC3 and mediates resistance to HDAC inhibitors by reprogramming the tumor immune environment in colorectal cancer
复制标题
检查点调节因子 B7x 受 HDAC3 表观遗传调节，并通过重新编程结直肠癌中的肿瘤免疫环境来介导对 HDAC 抑制剂的耐药性
DOI：
10.1038/s41419-020-02968-y
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发表时间：
2020-09-15
影响因子：
9
通讯作者：
Cui, Wei
中科院分区：
文献类型：
--
作者：
Li, Yuxin;Liu, Yao;Cui, Wei
HDAC抑制剂对于治疗淋巴瘤是有效的，但在治疗实体瘤中显示出有限的功效。在这里，我们研究了结直肠癌中HDAC抑制剂耐药与肿瘤免疫环境之间的关系。我们的数据表明，在研究的免疫因子中，B7 x表达在体外和体内HDAC耐药结直肠癌模型中增强。此外，基因操作结果表明，具有源自B7 x过表达CT-26结直肠癌细胞系的肿瘤的异种移植小鼠对HDAC抑制剂治疗具有抗性。值得注意的是，我们发现在结直肠癌细胞系和患者肿瘤中HDAC和B7 x表达之间存在负相关。此外，我们的数据表明，B7 x的表达升高与结直肠肿瘤患者的预后不良有关。有趣的是，用HDAC 3的特异性抑制剂或siRNA而不是HDAC 2、6和8处理导致结直肠癌细胞中B7 x表达的明显上调。此外，我们的数据显示，HDAC 3高表达和B7 x低表达的细胞系在编码B7 x的基因的启动子区域中乙酰化组蛋白H3的富集减少。这种模式通过添加HDAC 3抑制剂而逆转。从机制上讲，我们发现HDAC 3通过促进转录激活因子C/EBP-α与B7 x启动子区域的结合来调节B7 x的转录。重要的是，我们的数据表明，中和B7 x的抗体通过增加CD 4阳性和CD 8阳性T细胞的比率来增强结肠直肠癌异种移植模型和肺转移模型中对HDAC抑制剂的应答。总之，我们证明了B7 x在HDAC抑制剂耐药性中的作用，并确定了结直肠癌中B7 x失调的机制。我们的工作为克服HDAC抑制剂耐药性提供了一种新的策略。
HDAC inhibitors are efficacious for treating lymphoma, but display limited efficacy in treating solid tumors. Here, we investigated the relationship between HDAC inhibitor resistance and the tumor immune environment in colorectal cancer. Our data indicated that among the investigated immune factors, B7x expression was enhanced in HDAC inhibitor-resistant colorectal cancer models in vitro and in vivo. In addition, gene manipulation results demonstrated that xenograft mice with tumors derived from a B7x-overexpressing CT-26 colorectal cancer cell line were resistant to HDAC inhibitor treatment. Notably, we found that there is a negative relationship between HDAC and B7x expression in both colorectal cancer cell lines and patients’ tumors. Furthermore, our data indicated that elevated expression of B7x was related to a poor prognosis in colorectal tumor patients. Interestingly, treatment with a specific inhibitor or siRNA of HDAC3, but not HDAC2, 6, and 8, resulted in obvious upregulation of B7x expression in colorectal cancer cells. In addition, our data showed that a cell line with high HDAC3 expression and low B7x expression had decreased enrichment of acetylated histone H3 in the promoter region of the gene encoding B7x. This pattern was reversed by addition of HDAC3 inhibitors. Mechanistically, we found that HDAC3 regulated B7x transcription by promoting the binding of the transcription activator C/EBP-α with the B7x promoter region. Importantly, our data indicated that an antibody neutralizing B7x augmented the response to HDAC inhibitor in the colorectal cancer xenograft model and the lung metastasis model by increasing the ratios of both CD4-positive and CD8-positive T cells. In summary, we demonstrated a role of B7x in HDAC inhibitor resistance and identified the mechanism that dysregulates B7x in colorectal cancer. Our work provides a novel strategy to overcome HDAC inhibitor resistance.