| Autor: |
H. Kay Chung, Cong Liu, Eduardo Casillas, Brent Chick, Bryan Mcdonald, Jun Wang, Peixiang He, Ming Sun, Shixin Ma, Qiyuan Yang, Dan Chen, Filipe Hoffmann, Siva Karthik Varanasi, Victoria Tripple, Yuqing Hang, Ukrae H. Cho, Josephine Ho, April Williams, Yingxiao Wang, Diana Hargreaves, Susan M. Kaech, Wei Wang |
| Rok vydání: |
2023 |
| Předmět: |
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| Zdroj: |
bioRxiv |
| DOI: |
10.1101/2023.01.03.522354 |
| Popis: |
The same types of cells can assume diverse states with varying functionalities. Effective cell therapy can be achieved by specifically driving a desirable cell state, which requires the elucidation of key transcription factors (TFs). Here, we integrated epigenomic and transcriptomic data at the systems level to identify TFs that define different CD8+T cell states in an unbiased manner. These TF profiles can be used for cell state programming that aims to maximize the therapeutic potential of T cells. For example, T cells can be programmed to avoid a terminal exhaustion state (TexTerm), a dysfunctional T cell state that is often found in tumors or chronic infections. However, TexTermexhibits high similarity with the beneficial tissue-resident memory T states (TRM) in terms of their locations and transcription profiles. Our bioinformatic analysis predictedZscan20, a novel TF, to be uniquely active in TexTerm. Consistently,Zscan20knock-out thwarted the differentiation of TexTermin vivo, but not that of TRM. Furthermore, perturbation ofZscan20programs T cells into an effector-like state that confers superior tumor and virus control and synergizes with immune checkpoint therapy. We also identifiedJdp2andNfil3as powerful TexTermdrivers. In short, our multiomics-based approach discovered novel TFs that enhance anti-tumor immunity, and enable highly effective cell state programming.One sentence summaryMultiomics atlas enables the systematic identification of cell-state specifying transcription factors for therapeutic cell state programming. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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