Non-thermal plasma (NTP) shows promise as a potent anti-cancer therapy with both cytotoxic and immunomodulatory effects. In this study, we investigate the chemical and biological effects of NTP-induced oxidation on several key, determinant immune checkpoints of natural killer (NK) cell function. We used molecular dynamics (MD) and umbrella sampling simulations to investigate the effect of NTP-induced oxidative changes on the MHC-I complexes HLA-Cw4 and HLA-E. Our simulations indicate that these chemical alterations do not significantly affect the binding affinity of these markers to their corresponding NK cell receptor, which is supported with experimental read-outs of ligand expression on human head and neck squamous cell carcinoma cells after NTP application. Broadening our scope to other key ligands for NK cell reactivity, we demonstrate rapid reduction in CD155 and CD112, target ligands of the inhibitory TIGIT axis, and in immune checkpoint CD73 immediately after treatment. Besides these transient chemical alterations, the reactive species in NTP cause a cascade of downstream cellular reactions. This is underlined by the upregulation of the stress proteins MICA/B, potent ligands for NK cell activation, 24 h post treatment. Taken together, this work corroborates the immunomodulatory potential of NTP, and sheds light on the interaction mechanisms between NTP and cancer cells.

中文翻译：

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血浆诱导的氧化对 NK 细胞免疫检查点配体的影响：一种计算实验方法


非热血浆 （NTP） 有望成为一种具有细胞毒性和免疫调节作用的有效抗癌疗法。在这项研究中，我们研究了 NTP 诱导的氧化对自然杀伤 （NK） 细胞功能的几个关键决定性免疫检查点的化学和生物学效应。我们使用分子动力学 （MD） 和伞采样模拟来研究 NTP 诱导的氧化变化对 MHC-I 复合物 HLA-Cw4 和 HLA-E 的影响。我们的模拟表明，这些化学改变不会显着影响这些标志物与其相应的 NK 细胞受体的结合亲和力，NTP 应用后人头颈部鳞状细胞癌细胞配体表达的实验读数支持了这一点。将我们的范围扩大到 NK 细胞反应性的其他关键配体，我们证明了治疗后抑制性 TIGIT 轴的靶配体 CD155 和 CD112 以及免疫检查点 CD73 的快速减少。除了这些瞬时化学改变外，NTP 中的反应性物质还会引起下游细胞反应的级联反应。应激蛋白 MICA/B 的上调强调了这一点，MICA/B 是 NK 细胞活化的有效配体，处理后 24 小时。综上所述，这项工作证实了 NTP 的免疫调节潜力，并阐明了 NTP 与癌细胞之间的相互作用机制。