Abstract
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.
Highlights
Myeloid-derived suppressor cells (MDSCs) are potent immune suppressive cells that are induced by various pathological conditions, by cancer [18]
We show that LCL521 induces MDSC death through a mechanism that is independent of apoptosis and necroptosis
CD3+ T cells were purified from spleens of BALB/c mice and MDSCs were purified from tumor-bearing BALB/c mice
Summary
Myeloid-derived suppressor cells (MDSCs) are potent immune suppressive cells that are induced by various pathological conditions, by cancer [18]. By virtue of their functions as suppressors of anti-tumor immunity and producers of growth enhancers, MDSCs are considered as key targets in cancer immunotherapy [7, 13, 18,19,20,21,22,23]. Various pro-inflammatory factors, including IL-1β, IL-6, IL-10, prostaglandin E2 (PGE2), S100A8/9 proteins, GM-CSF, VEGF and HIF-1α, have been linked to MDSC accumulation [2, 26,27,28,29,30]. These studies clearly established the concept that tumor-induced inflammatory factors mediate MDSC accumulation in tumor-bearing hosts. Current approaches to suppress MDSCs have been largely focused on inhibition of MDSC differentiation and proliferation [31, 32]
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