Research Group PLASMANT, Department of Chemistry, University of Antwerp, 2610, Antwerp, Wilrijk, Belgium.
Research Group PLASMANT, Department of Chemistry, University of Antwerp, 2610, Antwerp, Wilrijk, Belgium; Center for Oncological Research (CORE), Integrated Personalized and Precision Oncology Network (IPPON), University of Antwerp, 2610, Antwerp, Wilrijk, Belgium.
Redox Biol. 2024 Nov;77:103381. doi: 10.1016/j.redox.2024.103381. Epub 2024 Oct 1.
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.
非热等离子体（NTP）显示出作为一种有效的抗癌治疗方法的潜力，具有细胞毒性和免疫调节作用。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免疫检查点的化学和生物学影响。我们使用分子动力学 (MD) 和伞状采样模拟来研究 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，这些化学变化不会显著影响这些标记物与相应 NK 细胞受体的结合亲和力，这与 NTP 应用后对人头颈鳞状细胞癌细胞上配体表达的实验读数相支持。扩大我们的研究范围到其他 NK 细胞反应的关键配体，我们证明了在治疗后立即迅速减少抑制性 TIGIT 轴的靶标配体 CD155 和 CD112，以及免疫检查点 CD73。除了这些短暂的化学变化外，NTP 中的反应性物质还会引发一连串下游的细胞反应。这一点在治疗后 24 小时，应激蛋白 MICA/B 的上调得到了强调，MICA/B 是 NK 细胞激活的有效配体。综上所述，这项工作证实了 NTP 的免疫调节潜力，并揭示了 NTP 与癌细胞之间的相互作用机制。
