Lin Abraham, Razzokov Jamoliddin, Verswyvel Hanne, Privat-Maldonado Angela, De Backer Joey, Yusupov Maksudbek, Cardenas De La Hoz Edgar, Ponsaerts Peter, Smits Evelien, Bogaerts Annemie
PLASMANT-Research Group, University of Antwerp, 2610 Antwerpen-Wilrijk, Belgium.
Center for Oncological Research (CORE), Integrated Personalized & Precision Oncology Network (IPPON), University of Antwerp, 2610 Antwerpen-Wilrijk, Belgium.
Cancers (Basel). 2021 Feb 2;13(3):579. doi: 10.3390/cancers13030579.
Non-thermal plasma (NTP) therapy has been emerging as a promising cancer treatment strategy, and recently, its ability to locally induce immunogenic cancer cell death is being unraveled. We hypothesized that the chemical species produced by NTP reduce immunosuppressive surface proteins and checkpoints that are overexpressed on cancerous cells. Here, 3D in vitro tumor models, an in vivo mouse model, and molecular dynamics simulations are used to investigate the effect of NTP on CD47, a key innate immune checkpoint. CD47 is immediately modulated after NTP treatment and simulations reveal the potential oxidized salt-bridges responsible for conformational changes. Umbrella sampling simulations of CD47 with its receptor, signal-regulatory protein alpha (SIRPα), demonstrate that the induced-conformational changes reduce its binding affinity. Taken together, this work provides new insight into fundamental, chemical NTP-cancer cell interaction mechanisms and a previously overlooked advantage of present NTP cancer therapy: reducing immunosuppressive signals on the surface of cancer cells.
非热等离子体（NTP）疗法已成为一种很有前景的癌症治疗策略，最近，其局部诱导免疫原性癌细胞死亡的能力正在被揭示。我们假设NTP产生的化学物质会减少癌细胞上过度表达的免疫抑制表面蛋白和检查点。在此，利用三维体外肿瘤模型、体内小鼠模型和分子动力学模拟来研究NTP对关键固有免疫检查点CD47的影响。NTP处理后CD47立即受到调节，模拟揭示了负责构象变化的潜在氧化盐桥。对CD47及其受体信号调节蛋白α（SIRPα）进行伞形抽样模拟表明，诱导的构象变化降低了其结合亲和力。综上所述，这项工作为NTP与癌细胞相互作用的基本化学机制提供了新的见解，以及目前NTP癌症治疗一个以前被忽视的优势：减少癌细胞表面的免疫抑制信号。
