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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 83907-83925 |
| Number of pages | 19 |
| Journal | Oncotarget |
| Volume | 7 |
| Issue number | 51 |
| DOIs | |
| State | Published - Jan 1 2016 |
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Keywords
- Autophagy flux
- Cathepsin
- Ceramide
- Immune response
- Immunity
- Immunology and Microbiology Section
- Lysosomal cell death
- MDSCs
ASJC Scopus subject areas
- Oncology
Cite this
Ceramide activates lysosomal cathepsin B and cathepsin D to attenuate autophagy and induces ER stress to suppress myeloidderived suppressor cells. / Liu, Feiyan; Li, Xia; Lu, Chunwan; Bai, Aiping; Bielawski, Jacek; Bielawska, Alicja; Marshall, Brendan; Schoenlein, Patricia V; Lebedyeva, Iryna Oleksandrivna; Liu, Kebin.
In: Oncotarget, Vol. 7, No. 51, 01.01.2016, p. 83907-83925.Research output: Contribution to journal › Article
}
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
PY - 2016/1/1
Y1 - 2016/1/1
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
VL - 7
SP - 83907
EP - 83925
JO - Oncotarget
JF - Oncotarget
SN - 1949-2553
IS - 51
ER -