Activating signals dominate inhibitory signals in CD137L/IL-15 activated natural killer cells.
Activating signals dominate inhibitory signals in CD137L/IL-15 activated natural killer cells.
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DOI：
10.1097/cji.0b013e31820d2a21
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发表时间：
2011-03
期刊：
影响因子：
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通讯作者：
Mackall CL
中科院分区：
文献类型：
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作者：
Zhang H;Cui Y;Voong N;Sabatino M;Stroncek DF;Morisot S;Civin CI;Wayne AS;Levine BL;Mackall CL
自然杀伤（NK）细胞可以介导有效的抗肿瘤作用，但调节肿瘤溶解效率的因素仍不清楚。异基因干细胞移植的研究强调了杀伤细胞免疫球蛋白样受体（KIR）错配在克服HLA介导的抑制信号中的重要作用。然而，其他激活和抑制信号也调节NK细胞的肿瘤溶解。我们用rhIL 15和表达CD 137 L和IL 15 R α的人工抗原呈递细胞（APC）在3周内激活和扩增外周血NK细胞（CD 137 L/IL 15 NK）达1000倍。与静息NK细胞相比，CD 137 L/IL 15 NK细胞显示KIR表达适度增加，NKG 2D、TRAIL和天然细胞毒性受体（NCR：NKp 30、NKp 44、NKp 46）显著增加。与静息NK细胞相比，CD 137 L/IL 15 NK细胞介导针对同种异体和自体肿瘤的增强的细胞毒性，并且KIR信号传导基本上不抑制细胞毒性。相反，CD 137 L/IL 15激活的NK细胞的肿瘤裂解主要由NCR信号传导驱动，因为NCR的阻断显著减少了广泛的肿瘤靶标的裂解。此外，CD 137 L/IL 15 NK细胞的肿瘤溶解与NCR表达水平紧密相关，其在NK活化后第8-10天达到峰值，并且随着NCR表达下降，细胞毒性在随后的日子里减少。我们得出的结论是，KIR错配并不是CD 137 L/IL 15 NK细胞杀死肿瘤的先决条件，并且NCR表达为在基于NK细胞的免疫治疗研究中预测CD 137 L/IL 15 NK细胞的效力提供了生物标志物。
Natural killer (NK) cells can mediate potent antitumor effects, but factors regulating the efficiency of tumor lysis remain unclear. Studies in allogeneic stem cell transplantation highlight an important role for killer cell immunoglobulin-like receptor (KIR) mismatch in overcoming HLA-mediated inhibitory signals. However other activating and inhibitory signals also modulate tumor lysis by NK cells. We used rhIL15 plus artificial antigen presenting cells (APCs) expressing CD137L and IL15Rα to activate and expand peripheral blood NK cells (CD137L/IL15 NK) up to 1000 fold in 3 weeks. Compared to resting NK cells, CD137L/IL15 NK cells demonstrate modest increases in KIR expression and substantial increases in NKG2D, TRAIL and natural cytotoxicity receptors (NCRs: NKp30, NKp44, NKp46). Compared to resting NK cells, CD137L/IL15 NK cells mediate enhanced cytotoxicity against allogeneic and autologous tumors and KIR signaling did not substantially inhibit cytotoxicity. Rather, tumor lysis by CD137L/IL15 activated NK cells was predominantly driven by NCR signaling since blockade of NCRs dramatically diminished lysis of a wide array of tumor targets. Furthermore, tumor lysis by CD137L/IL15 NK cells was tightly linked to NCR expression levels, which peaked on Day 8–10 following NK activation, and cytotoxicity diminished on subsequent days as NCR expression declined. We conclude that KIR mismatch is not a prerequisite for tumor killing by CD137L/IL15 NK cells and that NCR expression provides a biomarker for predicting potency of CD137L/IL15 NK cells in studies of NK cell based immunotherapy.