Chimeric Antigen Receptor-T Cells with 4-1BB Co-Stimulatory Domain Present a Superior Treatment Outcome than Those with CD28 Domain Based on Bioinformatics.
BACKGROUND
The second-generation CD19-chimeric antigen receptor (CAR)-T co-stimulatory domain that is commonly used in clinical practice is CD28 or 4-1BB. Previous studies have shown that the persistence of CAR-T in the 4-1BB co-stimulatory domain appears to be longer.


METHODS
The expression profile data of GSE65856 were obtained from GEO database. After data preprocessing, the differentially expressed genes (DEGs) between the mock CAR versus CD19-28z CAR T cells and mock CAR versus CD19-BBz CAR T cells were identified using the limma package. Subsequently, functional enrichment analysis of DEGs was performed using the DAVID tool. Then, the protein-protein international (PPI) network of these DEGs was visualized by Cytoscape, and the miRNA-target gene-disease regulatory networks were predicted using Webgestal.


RESULTS
A total of 18 common DEGs, 6 CD19-28z specific DEGs and 206 CD19-BBz specific DEGs were identified. Among CD19-28z specific DEGs, down-regulated PAX5 might be an important node in the PPI network and could be targeted by miR-496. In CD19-BBz group, JUN was a hub node in the PPI network and involved in the regulations of miR520D - early growth response gene 3 (EGR3)-JUN and mi-R489-AT-rich interaction domain 5A (ARID5A)-JUN networks.


CONCLUSION
The 4-1BB co-stimulatory domain might play in important role in the treatment of CAR-T via miR-520D-EGR3-JUN and miR489-ARID5A-JUN regulation network, while CD28 had a negative effect on CAR-T treatment.
['Zhong|Qi|Q|', 'Zhu|Yang-Min|YM|', 'Zheng|Li-Ling|LL|', 'Shen|Hui-Juan|HJ|', 'Ou|Rui-Ming|RM|', 'Liu|Zhi|Z|', 'She|Yan-Ling|YL|', 'Chen|Rui|R|', 'Li|Cheng|C|', 'Huang|Jing|J|', 'Yao|Meng-Dong|MD|', 'Zhang|Qing|Q|', 'Liu|Shuang|S|']
D000970:Antineoplastic Agents D018106:CD28 Antigens D019295:Computational Biology D016208:Databases, Factual D015972:Gene Expression Regulation, Neoplastic D006801:Humans D035683:MicroRNAs D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma D060066:Protein Interaction Maps D000076962:Receptors, Chimeric Antigen D016896:Treatment Outcome D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9
Differentially expressed genes CD19-28z GD2.BBz Protein-protein interaction