Vitamin D Receptor Antagonist MeTC7 Inhibits PD-L1
Negar Khazan, Emily R. Quarato, Niloy A. Singh, Cameron Snyder, Taylor Moore, John Miller, Masato Yasui, Yuki Teramoto, Takuro Goto, Sabeeha Reshi, Jennifer Hong, Naixin Zhang, Diya Pandey, Priyanka Srivastava, Alexandra Morell, Hiroki Kawano, Yuko Kawano, Thomas Conley, Deepak M. Sahasrabudhe, Naohiro Yano, Hiroshi Miyamoto, Omar S. Aljitawi, Jane L. Liesveld, Michael W. Becker, Laura M. Calvi, Alexander S. Zhovmer, Erdem D. Tabdanov, Nikolay V. Dokholyan, David C. Linehan, Jeanne N. Hansen, Scott A. Gerber, Ashoke Sharon, Manoj Kumar Khera, Peter W. Jurutka, Natacha Rochel, Kyu Kwang Kim, Rachael B. Rowswell-Turner, Rakesh K. Singh, Richard G. 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.