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