利用元图神经网络和通路串扰研究 CAR-T 治疗中的 CRS 相关细胞因子。
Investigation of CRS-associated cytokines in CAR-T therapy with meta-GNN and pathway crosstalk.
机构信息
College of Intelligent Systems Science and Engineering, Institute of Intelligent System and Bioinformatics, Harbin Engineering University, Harbin, 150001, China.
Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, Institute of Biomedical Engineering and Technology, East China Normal University, No. 3663 North Zhongshan Road, Shanghai, 200065, China.
出版信息
BMC Bioinformatics. 2022 Sep 13;23(1):373. doi: 10.1186/s12859-022-04917-2.
BACKGROUND
Chimeric antigen receptor T-cell (CAR-T) therapy is a new and efficient cellular immunotherapy. The therapy shows significant efficacy, but also has serious side effects, collectively known as cytokine release syndrome (CRS). At present, some CRS-related cytokines and their roles in CAR-T therapy have been confirmed by experimental studies. However, the mechanism of CRS remains to be fully understood.
METHODS
Based on big data for human protein interactions and meta-learning graph neural network, we employed known CRS-related cytokines to comprehensively investigate the CRS associated cytokines in CAR-T therapy through protein interactions. Subsequently, the clinical data for 119 patients who received CAR-T therapy were examined to validate our prediction results. Finally, we systematically explored the roles of the predicted cytokines in CRS occurrence by protein interaction network analysis, functional enrichment analysis, and pathway crosstalk analysis.
RESULTS
We identified some novel cytokines that would play important roles in biological process of CRS, and investigated the biological mechanism of CRS from the perspective of functional analysis.
CONCLUSIONS
128 cytokines and related molecules had been found to be closely related to CRS in CAR-T therapy, where several important ones such as IL6, IFN-γ, TNF-α, ICAM-1, VCAM-1 and VEGFA were highlighted, which can be the key factors to predict CRS.
背景
嵌合抗原受体 T 细胞（CAR-T）疗法是一种新的、有效的细胞免疫疗法。该疗法显示出显著的疗效，但也有严重的副作用，统称为细胞因子释放综合征（CRS）。目前，一些 CRS 相关细胞因子及其在 CAR-T 治疗中的作用已被实验研究证实。然而，CRS 的机制仍有待充分了解。
方法
基于人类蛋白质相互作用的大数据和元学习图神经网络，我们利用已知的 CRS 相关细胞因子，通过蛋白质相互作用，全面研究 CAR-T 治疗中与 CRS 相关的细胞因子。随后，我们对 119 名接受 CAR-T 治疗的患者的临床数据进行了检查，以验证我们的预测结果。最后，我们通过蛋白质相互作用网络分析、功能富集分析和途径串扰分析，系统地探讨了预测细胞因子在 CRS 发生中的作用。
结果
我们发现了一些新的细胞因子，它们在 CRS 的生物学过程中发挥重要作用，并从功能分析的角度探讨了 CRS 的生物学机制。
结论
在 CAR-T 治疗中发现 128 种细胞因子和相关分子与 CRS 密切相关，其中一些重要的细胞因子如 IL6、IFN-γ、TNF-α、ICAM-1、VCAM-1 和 VEGFA 被强调，它们可以作为预测 CRS 的关键因素。
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