Research Papers: Immunology:
Ceramide activates lysosomal cathepsin B and cathepsin D to attenuate autophagy and induces ER stress to suppress myeloid-derived suppressor cells
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Feiyan Liu1, Xia Li1, Chunwan Lu2,3, Aiping Bai4, Jacek Bielawski4, Alicja Bielawska4, Brendan Marshall5, Patricia V. Schoenlein5, Iryna O. Lebedyeva6 and Kebin Liu2,3,7
1 College of Life Sciences, Zhejiang University, Hangzhou, China
2 Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, GA, USA
3 Charlie Norwood VA Medical Center, Augusta, GA, USA
4 Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC, USA
5 Department of Cell Biology and Anatomy, Medical College of Georgia, Augusta, GA, USA
6 Department of Chemistry and Physics, Augusta University, Augusta, GA, USA
7 Georgia Cancer Center, Augusta University, Augusta, GA, USA
Feiyan Liu, email:
Keywords: MDSCs, cathepsin, ceramide, autophagy flux, Lysosomal cell death, Immunology and Microbiology Section, Immune response, Immunity
Received: October 10, 2016 Accepted: November 07, 2016 Published: November 17, 2016
Myeloid-derived suppressor cells (MDSCs) are immune suppressive cells that are hallmarks of human cancer. MDSCs inhibit cytotoxic T lymphocytes (CTLs) and NK cell functions to promote tumor immune escape and progression, and therefore are considered key targets in cancer immunotherapy. Recent studies determined a key role of the apoptosis pathways in tumor-induced MDSC homeostasis and it is known that ceramide plays a key role in regulation of mammalian cell apoptosis. In this study, we aimed to determine the efficacy and underlying molecular mechanism of ceramide in suppression of MDSCs. Treatment of tumor-bearing mice with LCL521, a lysosomotropic inhibitor of acid ceramidase, significantly decreased MDSC accumulation in vivo. Using a MDSC-like myeloid cell model, we determined that LCL521 targets lysosomes and increases total cellular C16 ceramide level. Although MDSC-like cells have functional apoptosis pathways, LCL521-induced MDSC death occurs in an apoptosis- and necroptosis-independent mechanism. LCL521 treatment resulted in an increase in the number of autophagic vesicles, heterolysosomes and swollen ERs. Finally, concomitant inhibition of cathepsin B and cathepsin D was required to significantly decrease LCL521-induced cell death. Our observations indicate that LCL521 targets lysosomes to activate cathepsin B and cathepsin D, resulting in interrupted autophagy and ER stress that culminates in MDSC death. Therefore, a ceramidase inhibitor is potentially an effective adjunct therapeutic agent for suppression of MDSCs to enhance the efficacy of CTL-based cancer immunotherapy.
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