Cancers (Jun 2023)
Vitamin D Receptor Antagonist MeTC7 Inhibits PD-L1
- Negar Khazan,
- Emily R. Quarato,
- Niloy A. Singh,
- Cameron W. A. Snyder,
- Taylor Moore,
- John P. 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 Aljitawi,
- Jane 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 K. Khera,
- Peter W. Jurutka,
- Natacha Rochel,
- Kyu Kwang Kim,
- Rachael B. Rowswell-Turner,
- Rakesh K. Singh,
- Richard G. Moore
Affiliations
- Negar Khazan
- Wilmot Cancer Institute and Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Rochester Medical Center, Rochester, NY 14642, USA
- Emily R. Quarato
- Department of Environmental Medicine, University of Rochester Medical Center, Rochester, NY 14642, USA
- Niloy A. Singh
- Wilmot Cancer Institute and Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Rochester Medical Center, Rochester, NY 14642, USA
- Cameron W. A. Snyder
- Wilmot Cancer Institute and Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Rochester Medical Center, Rochester, NY 14642, USA
- Taylor Moore
- Wilmot Cancer Institute and Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Rochester Medical Center, Rochester, NY 14642, USA
- John P. Miller
- Wilmot Cancer Institute and Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Rochester Medical Center, Rochester, NY 14642, USA
- Masato Yasui
- Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY 14642, USA
- Yuki Teramoto
- Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY 14642, USA
- Takuro Goto
- Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY 14642, USA
- Sabeeha Reshi
- School of Mathematical and Natural Sciences, University of Arizona College of Medicine, Phoenix, AZ 85004, USA
- Jennifer Hong
- School of Mathematical and Natural Sciences, University of Arizona College of Medicine, Phoenix, AZ 85004, USA
- Naixin Zhang
- Wilmot Cancer Institute and Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Rochester Medical Center, Rochester, NY 14642, USA
- Diya Pandey
- Wilmot Cancer Institute and Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Rochester Medical Center, Rochester, NY 14642, USA
- Priyanka Srivastava
- Wilmot Cancer Institute and Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Rochester Medical Center, Rochester, NY 14642, USA
- Alexandra Morell
- Wilmot Cancer Institute and Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Rochester Medical Center, Rochester, NY 14642, USA
- Hiroki Kawano
- Department of Medicine, Hematology/Oncology, University of Rochester Medical Center, Rochester, NY 14642, USA
- Yuko Kawano
- Department of Medicine, Hematology/Oncology, University of Rochester Medical Center, Rochester, NY 14642, USA
- Thomas Conley
- Department of Medicine, Hematology/Oncology, University of Rochester Medical Center, Rochester, NY 14642, USA
- Deepak M. Sahasrabudhe
- Department of Medicine, Hematology/Oncology, University of Rochester Medical Center, Rochester, NY 14642, USA
- Naohiro Yano
- Division of Surgical Research, Rhode Island Hospital, Brown University, Providence, RI 02912, USA
- Hiroshi Miyamoto
- Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY 14642, USA
- Omar Aljitawi
- Department of Medicine, Hematology/Oncology, University of Rochester Medical Center, Rochester, NY 14642, USA
- Jane Liesveld
- Department of Medicine, Hematology/Oncology, University of Rochester Medical Center, Rochester, NY 14642, USA
- Michael W. Becker
- Department of Medicine, Hematology/Oncology, University of Rochester Medical Center, Rochester, NY 14642, USA
- Laura M. Calvi
- Department of Medicine, Hematology/Oncology, University of Rochester Medical Center, Rochester, NY 14642, USA
- Alexander S. Zhovmer
- Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD 20993, USA
- Erdem D. Tabdanov
- CytoMechanobiology Laboratory, Department of Pharmacology, Penn State College of Medicine, Pennsylvania State University, Hershey, PA 17033, USA
- Nikolay V. Dokholyan
- Department of Pharmacology, Department of Biochemistry & Molecular Biology, Center for Translational Systems Research, Penn State College of Medicine, Pennsylvania State University, Hershey, PA 17033, USA
- David C. Linehan
- Division of Surgery, University of Rochester Medical Center, Rochester, NY 14642, USA
- Jeanne N. Hansen
- Department of Psychological and Brain Sciences, Colgate University, Hamilton, NY 13346, USA
- Scott A. Gerber
- Division of Surgery and Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY 14642, USA
- Ashoke Sharon
- Birla Institute of Technology, Ranchi 835215, India
- Manoj K. Khera
- Presude Lifesciences, Delhi 110075, India
- Peter W. Jurutka
- School of Mathematical and Natural Sciences, University of Arizona College of Medicine, Phoenix, AZ 85004, USA
- Natacha Rochel
- Institute of Genetics and of Molecular and Cellular Biology, 67400 Illkirch-Graffenstaden, France
- Kyu Kwang Kim
- Wilmot Cancer Institute and Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Rochester Medical Center, Rochester, NY 14642, USA
- Rachael B. Rowswell-Turner
- Wilmot Cancer Institute and Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Rochester Medical Center, Rochester, NY 14642, USA
- Rakesh K. Singh
- Wilmot Cancer Institute and Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Rochester Medical Center, Rochester, NY 14642, USA
- Richard G. Moore
- Wilmot Cancer Institute and Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Rochester Medical Center, Rochester, NY 14642, USA
- DOI
- https://doi.org/10.3390/cancers15133432
- Journal volume & issue
-
Vol. 15,
no. 13
p. 3432
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.
Keywords
