Mechanisms and immunogenicity of nsPEF-induced cell death in B16F10 melanoma tumors
Mechanisms and immunogenicity of nsPEF-induced cell death in B16F10 melanoma tumors
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DOI：
10.1038/s41598-018-36527-5
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发表时间：
2019-01-23
影响因子：
4.6
通讯作者：
Muratori, Claudia
中科院分区：
文献类型：
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作者：
Rossi, Alessandra;Pakhomova, Olga N.;Muratori, Claudia
越来越多的数据表明，一些癌症治疗方法可以通过诱导肿瘤免疫原性细胞死亡(ICD)来恢复抗癌免疫监视。纳秒脉冲电场(NsPEF)被证明可以有效地消融黑色素瘤。在本研究中，我们研究了nsPEF诱导B16F10黑色素瘤细胞死亡的机制和免疫原性。我们的数据表明，在体外，nsPEF(20-200,200 ns脉冲，7千伏/厘米，2赫兹)引起迅速的剂量依赖性的细胞死亡，这种死亡不伴随caspase激活或PARP裂解。体内实验证实在B16F10肿瘤中缺乏nsPEF诱导的细胞凋亡。NsPEF也未能触发与ICD相关的反应，如坏死性下垂和自噬。我们的结果表明，坏死是nsPEF诱导B16F10细胞死亡的主要机制。最后，我们比较了nsPEF(750,200 ns，25千伏/厘米，2赫兹)治疗的动物和手术切除肿瘤的动物的抗肿瘤免疫能力。与所有动物都发生肿瘤的幼稚组相比，nsPEF和手术分别保护了33%(6/18)和28.6%(4/14)的动物。我们的数据表明，在我们的实验条件下，nsPEF的局部消融作用得到了恢复，但并没有增强在荷瘤宿主中处于休眠状态的自然抗肿瘤免疫。
Accumulating data indicates that some cancer treatments can restore anticancer immunosurveillance through the induction of tumor immunogenic cell death (ICD). Nanosecond pulsed electric fields (nsPEF) have been shown to efficiently ablate melanoma tumors. In this study we investigated the mechanisms and immunogenicity of nsPEF-induced cell death in B16F10 melanoma tumors. Our data show that in vitro nsPEF (20-200, 200-ns pulses, 7 kV/cm, 2 Hz) caused a rapid dose-dependent cell death which was not accompanied by caspase activation or PARP cleavage. The lack of nsPEF-induced apoptosis was confirmed in vivo in B16F10 tumors. NsPEF also failed to trigger ICD-linked responses such as necroptosis and autophagy. Our results point at necrosis as the primary mechanism of cell death induced by nsPEF in B16F10 cells. We finally compared the antitumor immunity in animals treated with nsPEF (750, 200-ns, 25 kV/cm, 2 Hz) with animals were tumors were surgically removed. Compared to the naive group where all animals developed tumors, nsPEF and surgery protected 33% (6/18) and 28.6% (4/14) of the animals, respectively. Our data suggest that, under our experimental conditions, the local ablation by nsPEF restored but did not boost the natural antitumor immunity which stays dormant in the tumor-bearing host.