Bispecific and trispecific killer cell engagers directly activate human NK cells through CD16 signaling and induce cytotoxicity and cytokine production.
Bispecific and trispecific killer cell engagers directly activate human NK cells through CD16 signaling and induce cytotoxicity and cytokine production.
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DOI：
10.1158/1535-7163.mct-12-0692
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发表时间：
2012-12
影响因子：
5.7
通讯作者：
Miller JS
中科院分区：
文献类型：
--
作者：
Gleason MK;Verneris MR;Todhunter DA;Zhang B;McCullar V;Zhou SX;Panoskaltsis-Mortari A;Weiner LM;Vallera DA;Miller JS
本研究评估了双特异性和三特异性杀伤细胞因子（BiKE和TriKE）触发人NK细胞效应功能的机制，并研究了它们诱导NK细胞因子和趋化因子产生对抗人B细胞白血病的能力。我们检查了BiKE和TriKE通过直接CD 16信号传导触发NK细胞活化的能力，测量细胞内Ca 2+动员、溶解颗粒的分泌、靶细胞凋亡的诱导以及响应Raji细胞系和原发性白血病靶标的细胞因子和趋化因子的产生。由重组试剂触发的静息NK细胞通过直接CD 16信号传导导致细胞内Ca 2+动员。试剂处理的静息NK细胞与Raji靶标的共培养导致NK细胞脱粒和靶细胞死亡显著增加。BiKEs和TriKEs在高和低效应子与靶（E：T）比率下有效地介导Raji靶的NK细胞毒性，并且在人血清中培养24和48小时后保持功能稳定性。在存在重组试剂和Raji靶标的情况下，NK细胞产生IFN-γ、TNF-α、GM-CSF、IL-8、MIP-1α和RANTES的诱导差异。此外，静息NK细胞的试剂处理诱导了NK细胞脱粒的显著增加和针对主要ALL和CLL靶标的IFN-γ产生的增强。总之，BiKE和TriKE通过CD 16直接触发NK细胞活化，显著增加NK细胞对肿瘤靶点的细胞溶解活性和细胞因子产生，证明了它们增强NK细胞免疫疗法用于白血病和淋巴瘤的治疗潜力。
This study evaluates the mechanism by which bispecific and trispecific killer cell engagers (BiKEs and TriKEs) act to trigger human NK cell effector function and investigates their ability to induce NK cell cytokine and chemokine production against human B-cell leukemia. We examined the ability of BiKEs and TriKEs to trigger NK cell activation through direct CD16 signaling, measuring intracellular Ca2+ mobilization, secretion of lytic granules, induction of target cell apoptosis and production of cytokine and chemokines in response to the Raji cell line and primary leukemia targets. Resting NK cells triggered by the recombinant reagents led to intracellular Ca2+ mobilization through direct CD16 signaling. Co-culture of reagent-treated resting NK cells with Raji targets resulted in significant increases in NK cell degranulation and target cell death. BiKEs and TriKEs effectively mediated NK cytotoxicity of Raji targets at high and low effector-to-target (E:T) ratios and maintained functional stability after 24 and 48 hours of culture in human serum. NK cell production of IFN-γ, TNF-α, GM-CSF, IL-8, MIP-1α and RANTES was differentially induced in the presence of recombinant reagents and Raji targets. Moreover, significant increases in NK cell degranulation and enhancement of IFN-γ production against primary ALL and CLL targets were induced with reagent treatment of resting NK cells. In conclusion, BiKEs and TriKEs directly trigger NK cell activation through CD16, significantly increasing NK cell cytolytic activity and cytokine production against tumor targets, demonstrating their therapeutic potential for enhancing NK cell immunotherapies for leukemias and lymphomas.