Ceramide activates lysosomal cathepsin B and cathepsin D to attenuate autophagy and induces ER stress to suppress myeloid-derived suppressor cells.
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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DOI：
10.18632/oncotarget.13438
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发表时间：
2016-12-20
期刊：
影响因子：
--
通讯作者：
Liu K
中科院分区：
文献类型：
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作者：
Liu F;Li X;Lu C;Bai A;Bielawski J;Bielawska A;Marshall B;Schoenlein PV;Lebedyeva IO;Liu K
骨髓源性抑制细胞（MDSC）是免疫抑制细胞，是人类癌症的标志。MDSC抑制细胞毒性T淋巴细胞（CTL）和NK细胞功能以促进肿瘤免疫逃逸和进展，因此被认为是癌症免疫治疗的关键靶点。最近的研究确定了细胞凋亡途径在肿瘤诱导的MDSC稳态中的关键作用，并且已知神经酰胺在调节哺乳动物细胞凋亡中起关键作用。在这项研究中，我们的目的是确定神经酰胺抑制MDSC的有效性和潜在的分子机制。用LCL 521（一种酸性神经酰胺酶的亲溶酶体抑制剂）治疗荷瘤小鼠，可显著降低MDSC在体内的蓄积。使用MDSC样骨髓细胞模型，我们确定LCL 521靶向溶酶体并增加总细胞C16神经酰胺水平。虽然MDSC样细胞具有功能性凋亡途径，但LCL 521诱导的MDSC死亡发生在凋亡和坏死独立的机制中。LCL 521处理导致自噬囊泡、异溶酶体和肿胀ER的数量增加。最后，需要同时抑制组织蛋白酶B和组织蛋白酶D以显著降低LCL 521诱导的细胞死亡。我们的观察结果表明，LCL 521靶向溶酶体激活组织蛋白酶B和组织蛋白酶D，导致中断的自噬和ER应激，最终导致MDSC死亡。因此，神经酰胺酶抑制剂可能是用于抑制MDSC以增强基于CTL的癌症免疫疗法的功效的有效辅助治疗剂。
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.