Mechanism of Inhibition of the MeTC7 Ligand That Covalently Binds to VDR To Reduce PD-L1 Expression

Cancer-associated overexpression of the Vitamin D Receptor
(VDR)
is associated with good or poor prognosis, depending on the cancer
type and stage. Here, we show that VDR is overexpressed in ovarian
malignant tissues and upregulates PD-L1 surface expression in tumor
cells, enabling immune evasion by the tumors. MeTC7, a VDR antagonist,
has demonstrated strong inhibition of PD-L1 expression in vitro and
in vivo. Using structural mass spectrometry and biophysical methods,
we showed that MeTC7 binds covalently to VDR in the canonical ligand-binding
pocket. Using ligand excess, additional covalently bound molecules
were observed. Hydrogen–deuterium exchange mass spectrometry
revealed that MeTC7 binding prevents optimal folding of the C-terminal
region of VDR and impacts H10, which is part of the dimerization interface.
Overall, our findings highlight a new mechanism of action for a VDR
antagonist ligand and provide support for the use of the MeTC7 antagonist
to inhibit PD-L1 and block tumorigenesis.