Vitamin D Receptor Antagonist MeTC7 Inhibits PD-L1

Cancers

Negar Khazan , Emily Quarato , Niloy 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 Sahasrabudhe , Naohiro Yano , Hiroshi Miyamoto , Omar Aljitawi , Jane Liesveld , Michael Becker , Laura Calvi , Alexander Zhovmer , Erdem Tabdanov , Nikolay Dokholyan , David Linehan , Jeanne Hansen , Scott Gerber , Ashoke Sharon , Manoj Khera , Peter Jurutka , Natacha Rochel (1) , Kyu Kwang Kim , Rachael Rowswell-Turner , Rakesh Singh , Richard Moore

1 IGBMC - Institut de Génétique et de Biologie Moléculaire et Cellulaire

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.

Mots clés: PD-L1 AML MDS vitamin D VDR small molecule M2H assay efferocytosis; PD-L1; AML; MDS; vitamin D; VDR; small molecule; M2H assay; efferocytosis

Domaines: Sciences du Vivant [q-bio]

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⟩