RPN13/ADRM1 inhibitor reverses immunosuppression by myeloid-derived suppressor cells

// Ruey-Shyang Soong 1, 5, 6 , Ravi K. Anchoori 4 , Benjamin Yang 1 , Andrew Yang 1 , Ssu-Hsueh Tseng 1 , Liangmei He 1 , Ya-Chea Tsai 1 , Richard B.S. Roden 1, 2, 4 , Chien-Fu Hung 1, 4 1 Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD, United States 2 Department of Obstetrics and Gynecology, Johns Hopkins Medical Institutions, Baltimore, MD, United States 3 Department of Molecular Microbiology and Immunology, Johns Hopkins Medical Institutions, Baltimore, MD, United States 4 Department of Oncology, Johns Hopkins Medical Institutions, Baltimore, MD, United States 5 Department of General Surgery, Chang Gung Memorial Hospital at Keelung, Keelung City, Taiwan 6 Department of Chang Gung University, College of Medicine, Taoyuan, Taiwan Correspondence to: Chien-Fu Hung, email: chung2@jhmi.edu Keywords: RPN13, proteasome, immunosuppression, MDSCs, Stat3 Received: January 14, 2016      Accepted: September 12, 2016      Published: September 17, 2016 ABSTRACT 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.