Bortezomib treatment and regulatory T-cell depletion enhance the antitumor effects of adoptively infused NK cells
Bortezomib treatment and regulatory T-cell depletion enhance the antitumor effects of adoptively infused NK cells
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DOI：
10.1182/blood-2008-11-190421
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发表时间：
2009-06-11
期刊：
影响因子：
20.3
通讯作者：
Childs, Richard
中科院分区：
文献类型：
--
作者：
Lundqvist, Andreas;Yokoyama, Hisayuki;Childs, Richard
抑制受体的连接使自然杀伤(NK)细胞对自体肿瘤失去活性。最近，蛋白酶体抑制剂Bortezomib在体外被证明对自体NK细胞杀伤肿瘤敏感。在这里，我们展示了Bortezomib增强了同基因NK细胞输注在荷瘤动物中的抗肿瘤效果；这种效果在调节性T细胞(Treg细胞)耗尽的宿主中进一步增强。在体外，硼替佐米治疗的肿瘤具有较高的肿瘤坏死因子相关凋亡诱导配体(TRAIL)和穿孔素/颗粒酶介导的caspase-8活性，从而增强了其对NK细胞裂解的敏感性。对已建立肿瘤的小鼠的生物发光成像显示，与仅接受Bortezomib或NK细胞治疗的对照组相比，接受Bortezomib和同基因NK细胞治疗的小鼠肿瘤生长减少，生存时间延长。相反，当动物接受Bortezomib和穿孔素缺乏的NK细胞时，肿瘤的进展并没有延迟，表明药物诱导的NK细胞细胞毒性是通过穿孔素/颗粒酶介导的。此外，在注射NK细胞之前用抗CD25抗体根除宿主Treg细胞时，接受Bortezomib治疗的小鼠的肿瘤生长速度比没有去除Treg细胞的小鼠慢(肿瘤倍增时间分别为16.7天和4.9天；P=0.02)。这些发现表明，去除Treg细胞，然后用Bortezomib诱导肿瘤对自体NK细胞的增敏，可以作为治疗癌症的一种新策略。(血。2009；113：6120-6127)
Ligation of inhibitory receptors renders natural killer (NK) cells inactive against autologous tumors. Recently, the proteasome inhibitor bortezomib was shown to sensitize tumors to autologous NK-cell cytotoxicity in vitro. Here, we show bortezomib augments the antitumor effects of syngeneic NK-cell infusions in tumor-bearing animals; this effect is further enhanced in regulatory T cell (Treg cell)depleted hosts. In vitro, bortezomib-treated tumors had higher tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and perforin/granzyme-mediated caspase-8 activity, which enhanced their susceptibility to NK-cell lysis. Bioluminescence imaging of mice with established tumors showed treatment with bortezomib and syngeneic NK cells reduced tumor growth and prolonged survival compared with controls receiving bortezomib or NK cells alone. In contrast, tumor progression was not delayed when animals received bortezomib and perforin-deficient NK cells, showing drug-induced augmentation in NK-cell cytotoxicity was mediated through perforin/granzyme. Furthermore, tumor growth was slower in bortezomib-treated recipients when host Treg cells were eradicated with anti-CD25 antibody before infusing NK cells compared with mice without Treg-cell ablation (tumor doubling time, 16.7 vs 4.9 days, respectively; P = .02). These findings suggest that depletion of Treg cells followed by bortezomib-induced tumor sensitization to autologous NK cells could be used as a novel strategy to treat cancer. (Blood. 2009; 113: 6120-6127)