RPN13/ADRM1 inhibitor reverses immunosuppression by myeloid-derived suppressor cells
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Ruey-Shyang Soong1,5,6, Ravi K. Anchoori4, Benjamin Yang1, Andrew Yang1, Ssu-Hsueh Tseng1, Liangmei He1, Ya-Chea Tsai1, Richard B.S. Roden1,2,4, Chien-Fu Hung1,4
1Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD, United States
2Department of Obstetrics and Gynecology, Johns Hopkins Medical Institutions, Baltimore, MD, United States
3Department of Molecular Microbiology and Immunology, Johns Hopkins Medical Institutions, Baltimore, MD, United States
4Department of Oncology, Johns Hopkins Medical Institutions, Baltimore, MD, United States
5Department of General Surgery, Chang Gung Memorial Hospital at Keelung, Keelung City, Taiwan
6Department of Chang Gung University, College of Medicine, Taoyuan, Taiwan
Chien-Fu Hung, email: [email protected]
Keywords: RPN13, proteasome, immunosuppression, MDSCs, Stat3
Received: January 14, 2016 Accepted: September 12, 2016 Published: September 17, 2016
Myeloid-derived-suppressor cells (MDSCs) are key mediators of immune suppression in the ovarian tumor microenvironment. Modulation of MDSC function to relieve immunosuppression may enhance the immunologic clearance of tumors. The bis-benzylidine piperidone RA190 binds to the ubiquitin receptor RPN13/ADRM1 on the 19S regulatory particle of the proteasome and directly kills ovarian cancer cells by triggering proteotoxic stress. Here we examine the effect of RA190 treatment on the immunosuppression induced by MDSCs in the tumor microenvironment, specifically on the immunosuppression induced by MDSCs. We show that RA190 reduces the expression of Stat3 and the levels of key immunosuppressive enzymes and cytokines arginase, iNOS, and IL-10 in MDSCs, while boosting expression of the immunostimulatory cytokine IL-12. Furthermore, we show that the RA190-treated MDSCs lost their capacity to suppress CD8+ T cell function. Finally, we show that RA190 treatment of mice bearing syngeneic ovarian tumor elicits potent CD8+ T cell antitumor immune responses and improves tumor control and survival. These data suggest the potential of RA190 for ovarian cancer treatment by both direct killing of tumor cells via proteasome inhibition and relief of MDSC-mediated suppression of CD8 T cell-dependent antitumor immunity elicited by the apoptotic tumor cells.
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