TY - JOUR
T1 - Ceramide activates lysosomal cathepsin B and cathepsin D to attenuate autophagy and induces ER stress to suppress myeloidderived suppressor cells
AU - Liu, Feiyan
AU - Li, Xia
AU - Lu, Chunwan
AU - Bai, Aiping
AU - Bielawski, Jacek
AU - Bielawska, Alicja
AU - Marshall, Brendan
AU - Schoenlein, Patricia V
AU - Lebedyeva, Iryna Oleksandrivna
AU - Liu, Kebin
N1 - Funding Information:
We thank Dr. Jeanene Pihkala for assistance in cell sorting. National Natural Science Foundation of China 31570811 (F.L.), National Institute of Health CA133085 (K.L.) and VA Merit Review Award (BX001962 (K.L.).
PY - 2016
Y1 - 2016
N2 - 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.
AB - 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.
KW - Autophagy flux
KW - Cathepsin
KW - Ceramide
KW - Immune response
KW - Immunity
KW - Immunology and Microbiology Section
KW - Lysosomal cell death
KW - MDSCs
UR - http://www.scopus.com/inward/record.url?scp=85007482646&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85007482646&partnerID=8YFLogxK
U2 - 10.18632/oncotarget.13438
DO - 10.18632/oncotarget.13438
M3 - Article
C2 - 27880732
AN - SCOPUS:85007482646
SN - 1949-2553
VL - 7
SP - 83907
EP - 83925
JO - Oncotarget
JF - Oncotarget
IS - 51
ER -