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Journal Articles Cancers Year : 2023

Vitamin D Receptor Antagonist MeTC7 Inhibits PD-L1

Cancers

Negar Khazan
  • Function : Author
Emily Quarato
Niloy Singh
  • Function : Author
Cameron Snyder
Taylor Moore
  • Function : Author
John Miller
  • Function : Author
Masato Yasui
  • Function : Author
Yuki Teramoto
Takuro Goto
  • Function : Author
Sabeeha Reshi
  • Function : Author
Jennifer Hong
  • Function : Author
Naixin Zhang
  • Function : Author
Diya Pandey
  • Function : Author
Priyanka Srivastava
  • Function : Author
Alexandra Morell
  • Function : Author
Hiroki Kawano
  • Function : Author
Yuko Kawano
  • Function : Author
Thomas Conley
  • Function : Author
Deepak Sahasrabudhe
  • Function : Author
Naohiro Yano
Hiroshi Miyamoto
  • Function : Author
Omar Aljitawi
  • Function : Author
Jane Liesveld
  • Function : Author
Michael Becker
  • Function : Author
Laura Calvi
  • Function : Author
Alexander Zhovmer
  • Function : Author
Erdem Tabdanov
  • Function : Author
Nikolay Dokholyan
David Linehan
  • Function : Author
Jeanne Hansen
Scott Gerber
  • Function : Author
Ashoke Sharon
  • Function : Author
Manoj Khera
  • Function : Author
Peter Jurutka
Kyu Kwang Kim
  • Function : Author
Rachael Rowswell-Turner
  • Function : Author
Rakesh Singh
Richard Moore

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 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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Dates and versions

hal-04274207 , version 1 (07-11-2023)

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Negar Khazan, Emily Quarato, Niloy Singh, Cameron Snyder, Taylor Moore, et al.. Vitamin D Receptor Antagonist MeTC7 Inhibits PD-L1. Cancers, 2023, 15 (13), pp.3432. ⟨10.3390/cancers15133432⟩. ⟨hal-04274207⟩
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