Loss of VGLL4 suppresses tumor PD-L1 expression and immune evasion
Loss of VGLL4 suppresses tumor PD-L1 expression and immune evasion
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VGLL4 的缺失会抑制肿瘤 PD-L1 的表达和免疫逃避。
DOI：
10.15252/embj.201899506
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发表时间：
2019-01-03
期刊：
影响因子：
11.4
通讯作者：
Song, Hai
中科院分区：
文献类型：
--
作者：
Wu, Ailing;Wu, Qingzhe;Song, Hai
靶向免疫检查点，如PD-L1及其受体PD-1，为治疗癌症开辟了新途径。了解PD-L1和PD-1的调节机制将提高PD-1/PD-L1阻断剂在癌症患者中的临床应答率和疗效，并开发组合策略。VGLL 4通过与雅普竞争结合TEAD来抑制YAP诱导的细胞增殖和肿瘤发生。然而，VGLL 4是否在抗肿瘤免疫中起作用在很大程度上是未知的。在此，我们发现Vgll 4的破坏导致鼠同基因模型中有效的T细胞介导的肿瘤消退。VGLL 4缺陷会降低肿瘤细胞中PD-L1的表达。VGLL 4与IRF 2BP 2相互作用并通过抑制蛋白酶体介导的蛋白质降解来促进其蛋白质稳定性。IRF 2BP 2的缺失导致IRF 2（一种转录阻遏物）与PD-L1启动子的持续结合。此外，雅普通过抑制雅普靶基因miR-130 a对VGLL 4和IRF 1的表达，部分抑制IFN γ诱导的PD-L1表达。我们的研究确定VGLL 4是PD-L1表达的重要调节因子，并强调了VGLL 4和雅普在肿瘤免疫调节中的核心作用。
Targeting immune checkpoints, such as PD-L1 and its receptor PD-1, has opened a new avenue for treating cancers. Understanding the regulatory mechanism of PD-L1 and PD-1 will improve the clinical response rate and efficacy of PD-1/PD-L1 blockade in cancer patients and the development of combinatorial strategies. VGLL4 inhibits YAP-induced cell proliferation and tumorigenesis through competition with YAP for binding to TEADs. However, whether VGLL4 has a role in anti-tumor immunity is largely unknown. Here, we found that disruption of Vgll4 results in potent T cell-mediated tumor regression in murine syngeneic models. VGLL4 deficiency reduces PD-L1 expression in tumor cells. VGLL4 interacts with IRF2BP2 and promotes its protein stability through inhibiting proteasome-mediated protein degradation. Loss of IRF2BP2 results in persistent binding of IRF2, a transcriptional repressor, to PD-L1 promoter. In addition, YAP inhibits IFN gamma-inducible PD-L1 expression partially through suppressing the expression of VGLL4 and IRF1 by YAP target gene miR-130a. Our study identifies VGLL4 as an important regulator of PD-L1 expression and highlights a central role of VGLL4 and YAP in the regulation of tumor immunity.