Vitamin D Receptor Antagonist MeTC7 Inhibits PD-L1
In: Cancers (Basel, 2023
academicJournal
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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. ABSTRACT: 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 ...
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Vitamin D Receptor Antagonist MeTC7 Inhibits PD-L1
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Autor/in / Beteiligte Person: | 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 ; Miyamoto, Hiroshi ; Aljitawi, Omar ; Liesveld, Jane ; Becker, Michael W. ; Calvi, Laura M. ; Zhovmer, Alexander S. ; Tabdanov, Erdem D. ; Dokholyan, Nikolay V. ; Linehan, David C. ; Hansen, Jeanne N. ; Gerber, Scott A. ; Sharon, Ashoke ; Khera, Manoj K. ; Jurutka, Peter W. ; Rochel, Natacha ; Kim, Kyu Kwang ; Rowswell-Turner, Rachael B. ; Singh, Rakesh K. ; Moore, Richard G. |
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Zeitschrift: | Cancers (Basel, 2023 |
Veröffentlichung: | MDPI, 2023 |
Medientyp: | academicJournal |
DOI: | 10.3390/cancers15133432 |
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