Vitamin D Receptor Antagonist MeTC7 Inhibits PD-L1.
Vitamin D Receptor Antagonist MeTC7 Inhibits PD-L1.
复制标题
维生素D受体拮抗剂METC7抑制PD-L1。
DOI：
10.3390/cancers15133432
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发表时间：
2023-06-30
期刊：
影响因子：
5.2
通讯作者：
Moore, Richard G. G.
中科院分区：
文献类型：
--
作者：
Khazan, Negar;Quarato, Emily R. R.;Singh, Niloy A. A.;Snyder, Cameron W. A.;Moore, Taylor;Miller, John P. P.;Yasui, Masato;Teramoto, Yuki;Goto, Takuro;Reshi, Sabeeha;Hong, Jennifer;Zhang, Naixin;Pandey, Diya;Srivastava, Priyanka;Morell, Alexandra;Kawano, Hiroki;Kawano, Yuko;Conley, Thomas;Sahasrabudhe, Deepak M. M.;Yano, Naohiro;Miyamoto, Hiroshi;Aljitawi, Omar;Liesveld, Jane;Becker, Michael W. W.;Calvi, Laura M. M.;Zhovmer, Alexander S. S.;Tabdanov, Erdem D. D.;Dokholyan, Nikolay V. V.;Linehan, David C. C.;Hansen, Jeanne N. N.;Gerber, Scott A. A.;Sharon, Ashoke;Khera, Manoj K. K.;Jurutka, Peter W. W.;Rochel, Natacha;Kim, Kyu Kwang;Rowswell-Turner, Rachael B. B.;Singh, Rakesh K. K.;Moore, Richard G. G.
程序性死亡配体1（PD-L1）使肿瘤的免疫逃避成为可能。靶向PD-L1/PD-1的抗体在合格患者中表现出持久的应答。然而，抗体会导致危及生命的毒性。靶向PD-L1的小分子，或PD-L1或PD-L1/PD-1轴的驱动因子，正在被探索作为替代方案。因此，将维生素D/维生素D受体（VDR）鉴定为AML中PD-L1表达的驱动因子，显著增强了我们对AML和胰腺和卵巢恶性肿瘤中PD-L1驱动的免疫逃避起源的理解，其中观察到类似的转录调控。为了靶向维生素D/VDR，我们开发了MeTC 7，它在体外和体内抑制PD-L1表达，并提供了一种阻断PD-L1/PD-1驱动的肿瘤发生的新方法。PD-L1的小分子抑制剂被认为可以控制肿瘤中的免疫逃避，类似于靶向PD-L1/PD-1免疫检查点轴的抗体。然而，开发小分子PD-L1抑制剂需要鉴定靶向PD-L1诱导剂。在这项研究中，使用染色质免疫沉淀（ChIP）测定和siRNA，我们证明了维生素D/VDR调节急性髓性白血病（AML）和骨髓增生异常综合征（MDS）细胞中PD-L1的表达。我们已经检查了VDR拮抗剂MeTC 7是否可以抑制PD-L1。为了确保MeTC 7抑制VDR/PD-L1而不产生脱靶效应，我们在哺乳动物双杂交（M2 H）试验中利用VDR-RXR、RXR-RXR和VDR共激活因子的配体依赖性二聚化，研究了MeTC 7对VDR的竞争性抑制。MeTC 7选择性抑制VDR，抑制PD-L1表达（保留PD-L2），并抑制AML细胞的细胞活力、克隆形成和异种移植物生长。MeTC 7阻断AML/间充质干细胞（MSC）粘附并增加THP-1 AML细胞的促凋亡效率。此外，利用在放射治疗（RT）下体内发生VDR/PD-L1共上调的同基因结直肠癌模型，MeTC 7抑制PD-L1并增强表达淋巴活化抗原-CD 69的肿瘤内CD 8 +T细胞。总之，MeTC 7是一种具有临床潜力的PD-L1小分子抑制剂。
Programmed death-ligand 1 (PD-L1) enables immune evasion of tumors. Antibodies targeting PD-L1/PD-1 exhibit durable responses in eligible patients. However, antibodies cause life-threatening toxicities. Small molecules targeting PD-L1, or the drivers of PD-L1 or PD-L1/PD-1 axis, are being explored as alternatives. Thus, identifying vitamin D/vitamin D receptor (VDR) as the driver of PD-L1 expression in AML significantly enhances our understanding of the origin of PD-L1-driven immune evasions in AML and malignancies of pancreas and ovaries, where similar transcriptional regulation has been observed. To target vitamin D/VDR, we have developed MeTC7, which inhibits PD-L1 expression in vitro and in vivo and provides a new approach to block PD-L1/PD-1-driven tumorigenesis. Small-molecule inhibitors of PD-L1 are postulated to control immune evasion in tumors similar to antibodies that target the PD-L1/PD-1 immune checkpoint axis. However, the identity of targetable PD-L1 inducers is required to develop small-molecule PD-L1 inhibitors. In this study, using chromatin immunoprecipitation (ChIP) assay and siRNA, we demonstrate that vitamin D/VDR regulates PD-L1 expression in acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) cells. We have examined whether a VDR antagonist, MeTC7, can inhibit PD-L1. To ensure that MeTC7 inhibits VDR/PD-L1 without off-target effects, we examined competitive inhibition of VDR by MeTC7, utilizing ligand-dependent dimerization of VDR-RXR, RXR-RXR, and VDR-coactivators in a mammalian 2-hybrid (M2H) assay. MeTC7 inhibits VDR selectively, suppresses PD-L1 expression sparing PD-L2, and inhibits the cell viability, clonogenicity, and xenograft growth of AML cells. MeTC7 blocks AML/mesenchymal stem cells (MSCs) adhesion and increases the efferocytotic efficiency of THP-1 AML cells. Additionally, utilizing a syngeneic colorectal cancer model in which VDR/PD-L1 co-upregulation occurs in vivo under radiation therapy (RT), MeTC7 inhibits PD-L1 and enhances intra-tumoral CD8+T cells expressing lymphoid activation antigen-CD69. Taken together, MeTC7 is a promising small-molecule inhibitor of PD-L1 with clinical potential.
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影响因子：
4.8
作者：
Dimitrov, Vassil;Bouttier, Manuella;White, John H.
通讯作者：
White, John H.
影响因子：
7.3
作者：
Guzik, Katarzyna;Zak, Krzysztof M.;Holak, Tad A.
通讯作者：
Holak, Tad A.
DOI：
10.1056/nejmoa1200694
发表时间：
2012-06-28
期刊：
The New England journal of medicine
影响因子：
--
作者：
Brahmer JR;Tykodi SS;Chow LQ;Hwu WJ;Topalian SL;Hwu P;Drake CG;Camacho LH;Kauh J;Odunsi K;Pitot HC;Hamid O;Bhatia S;Martins R;Eaton K;Chen S;Salay TM;Alaparthy S;Grosso JF;Korman AJ;Parker SM;Agrawal S;Goldberg SM;Pardoll DM;Gupta A;Wigginton JM
通讯作者：
Wigginton JM
视黄酸相关孤儿受体 C 通过 PD-L1/ITGB6/STAT3 信号轴调节膀胱癌的增殖、糖酵解和化疗耐药
影响因子：
11.2
作者：
Cao, Dalong;Qi, Zihao;Wang, Ziliang
通讯作者：
Wang, Ziliang
影响因子：
5.2
作者：
Cantorna MT
通讯作者：
Cantorna MT