التفاصيل البيبلوغرافية
| العنوان: |
Vitamin D Receptor Antagonist MeTC7 Inhibits PD-L1. |
| المؤلفون: |
Khazan, Negar, Quarato, Emily R., Singh, Niloy A., Snyder, Cameron W. A., Moore, Taylor, Miller, John 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., Yano, Naohiro |
| المصدر: |
Cancers; Jul2023, Vol. 15 Issue 13, p3432, 17p |
| مصطلحات موضوعية: |
MYELODYSPLASTIC syndromes, IN vitro studies, SMALL molecules, PROGRAMMED death-ligand 1, IN vivo studies, CARCINOGENESIS, ANIMAL experimentation, CELL receptors, PRECIPITIN tests, VITAMIN D, GENE expression, CELL survival, RESEARCH funding, SEX chromatin, BIOLOGICAL assay, MICE, CHEMICAL inhibitors |
| مستخلص: |
Simple Summary: 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. [ABSTRACT FROM AUTHOR] |
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| قاعدة البيانات: |
Complementary Index |
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