Membrane-proximal TRAIL species are incapable of inducing short circuit apoptosis signaling: Implications for drug development and basic cytokine biology.
Membrane-proximal TRAIL species are incapable of inducing short circuit apoptosis signaling: Implications for drug development and basic cytokine biology.
复制标题
膜近端 TRAIL 物种无法诱导短路凋亡信号传导：对药物开发和基本细胞因子生物学的影响。
DOI：
10.1038/srep22661
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发表时间：
2016
影响因子：
4.6
通讯作者：
Spitzer,Dirk
中科院分区：
文献类型：
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作者：
Tatzel,Katharina;Kuroki,Lindsay;Dmitriev,Igor;Kashentseva,Elena;Curiel,DavidT;Goedegebuure,SPeter;Powell,MatthewA;Mutch,DavidG;Hawkins,WilliamG;Spitzer,Dirk
TRAIL作为一种重组癌症治疗剂继续引起人们的极大兴趣，而天然细胞因子本身在以膜锚定形式在活化的免疫效应细胞上表达时发挥重要的肿瘤监视功能。我们最近开发了遗传稳定的TRAIL平台TR 3，以努力改善与目前可用的药物变体相关的限制。虽然在使用单链抗体（scFv）递送形式（SS-TR 3）表征间皮素靶向TR 3变体的过程中，我们发现与非靶向TR 3相比，膜束缚细胞因子的活性谱大幅增加。然而，细胞死亡完全通过旁观者机制进行，并保护间皮素阳性靶点免于凋亡，而不是导致其消除。将间隔子掺入间皮素表面抗原或癌症药物本身将SS-TR 3转化为顺式作用表型。用膜锚定的TR 3变体和天然细胞因子的进一步实验证实了我们的假设，即膜近端TRAIL种类缺乏物理接合在相同细胞膜上共表达的其同源受体的能力。我们的研究结果不仅为TNF超家族的代表性成员的配体和受体的“和平”共存提供了解释，而且为我们设计基于活性增强的TR 3的癌症治疗提供了重要线索。
TRAIL continues to garner substantial interest as a recombinant cancer therapeutic while the native cytokine itself serves important tumor surveillance functions when expressed in membrane-anchored form on activated immune effector cells. We have recently developed the genetically stabilized TRAIL platform TR3 in efforts to improve the limitations associated with currently available drug variants. While in the process of characterizing mesothelin-targeted TR3 variants using a single chain antibody (scFv) delivery format (SS-TR3), we discovered that the membrane-tethered cytokine had a substantially increased activity profile compared to non-targeted TR3. However, cell death proceeded exclusively via a bystander mechanism and protected the mesothelin-positive targets from apoptosis rather than leading to their elimination. Incorporation of a spacer-into the mesothelin surface antigen or the cancer drug itself-converted SS-TR3 into a cis-acting phenotype. Further experiments with membrane-anchored TR3 variants and the native cytokine confirmed our hypothesis that membrane-proximal TRAIL species lack the capacity to physically engage their cognate receptors coexpressed on the same cell membrane. Our findings not only provide an explanation for the “peaceful” coexistence of ligand and receptor of a representative member of the TNF superfamily but give us vital clues for the design of activity-enhanced TR3-based cancer therapeutics.