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Oxidation of Innate Immune Checkpoint CD47 on Cancer Cells with Non-Thermal Plasma

非熱等離子體對癌細(xì)胞的先天免疫檢查點(diǎn) CD47 的氧化

Non-thermal plasma is being developed for cancer immunotherapy. The aim of our study was to determine the effect of non-thermal plasma on immunosuppressive immune checkpoint, CD47. The direct effect of non-thermal plasma on CD47 was measured in vitro and in vivo, and the mechanism of action was studied in silico. Non-thermal plasma immediately oxidized CD47, suggesting a dual role of non-thermal plasma therapy to simultaneously increase immunogenic signals and reduce immunosuppressive ones.

正在開發(fā)用于癌癥免疫治療的非熱等離子體。我們研究的目的是確定非熱等離子體對免疫抑制性免疫檢查點(diǎn) CD47 的影響。在體外和體內(nèi)測量了非熱等離子體對 CD47 的直接影響，并在計(jì)算機(jī)上研究了作用機(jī)制。非熱等離子體立即氧化 CD47，表明非熱等離子體療法具有同時(shí)增加免疫原性信號和減少免疫抑制信號的雙重作用。

高效搖瓶

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.

非熱等離子體 (NTP) 療法已成為一種有前途的癌癥治療策略，最近，其局部誘導(dǎo)免疫原性癌細(xì)胞死亡的能力正在被揭示。我們假設(shè) NTP 產(chǎn)生的化學(xué)物質(zhì)減少了在癌細(xì)胞上過度表達(dá)的免疫抑制性表面蛋白和檢查點(diǎn)。在這里，3D 體外腫瘤模型、體內(nèi)小鼠模型和分子動(dòng)力學(xué)模擬用于研究 NTP 對關(guān)鍵先天免疫檢查點(diǎn) CD47 的影響。CD47 在 NTP 處理后立即被調(diào)制，模擬揭示了導(dǎo)致構(gòu)象變化的潛在氧化鹽橋。CD47 及其受體信號調(diào)節(jié)蛋白α (SIRPα) 的傘形采樣模擬表明，誘導(dǎo)的構(gòu)象變化降低了其結(jié)合親和力。

三角細(xì)胞搖瓶

In summary, we demonstrate that NTP is able to modulate the immune checkpoint CD47 in 3D cancer spheroids and tumors. IHC analysis showed that all 3 human cell lines of glioblastoma, melanoma, and head and neck squamous cell carcinoma had reduced CD47 expression immediately after NTP treatment compared to controls. Due to the timing of treatment and analysis, this was likely due to oxidation of the protein and was further studied in silico. In silico evaluation revealed higher fluctuations in the RMSD of the backbone atoms of oxidized CD47 compared to the native, which indicate conformational changes to the protein. MD simulations with CD47 and its receptor SIRPα revealed 10 inter-protein salt bridges that were modified following oxidation of CD47, with Lys39-Asp100 and Lys41-Asp100 being completely disrupted. This lead to weaker binding affinity to SIRPα as shown via US simulations and the obtained FEPs. Taken together, our results suggest a role of non-thermal plasma therapy to reduce immunosuppressive signals on tumor cells. The clinical impact of this paradigm requires further investigation.

T75 細(xì)胞培養(yǎng)瓶

總之，我們證明 NTP 能夠調(diào)節(jié) 3D 癌癥球體和腫瘤中的免疫檢查點(diǎn) CD47。IHC 分析顯示，與對照相比，在 NTP 治療后，膠質(zhì)母細(xì)胞瘤、黑色素瘤和頭頸部鱗狀細(xì)胞癌的所有 3 種人類細(xì)胞系都立即降低了 CD47 表達(dá)。由于處理和分析的時(shí)間安排，這可能是由于蛋白質(zhì)的氧化，并在計(jì)算機(jī)上進(jìn)行了進(jìn)一步研究。計(jì)算機(jī)評估顯示，與天然相比，氧化 CD47 的主鏈原子的 RMSD 波動(dòng)更大，這表明蛋白質(zhì)的構(gòu)象發(fā)生了變化。CD47 及其受體 SIRPα 的 MD 模擬揭示了 10 個(gè)蛋白質(zhì)間鹽橋，這些鹽橋在 CD47 氧化后被修飾，Lys39-Asp100 和 Lys41-Asp100 被完全破壞。如美國模擬和獲得的 FEP 所示，這導(dǎo)致對 SIRPα 的結(jié)合親和力較弱?？傊覀兊难芯拷Y(jié)果表明非熱等離子體療法可以減少腫瘤細(xì)胞上的免疫抑制信號。這種范式的臨床影響需要進(jìn)一步研究。

關(guān)鍵詞： 非熱等離子體,介質(zhì)阻擋放電,癌癥治療,免疫檢查點(diǎn),CD47 ,分子動(dòng)力學(xué)模擬,活性氧, non-thermal plasma,dielectric barrier discharge,cancer therapy,immune checkpoint,CD47, molecular dynamic simulation,reactive oxygen species

來源：MDPI https://www.mdpi.com/2072-6694/13/3/579/htm