2023-11-09 デューク大学(Duke)
◆この研究では、BATF3と呼ばれるマスターレギュレーターが特定され、T細胞療法の向上のために実験された。これらの新たな標的とその同定、テスト、操作手法は、現在使用されているあらゆるT細胞がん治療をより強力にする可能性があり、他の進展と組み合わせることで、汎用性のある治療法への展開や自己免疫疾患など他の疾患への拡大が可能とされる。Nature Geneticsに発表されたこれらの結果は、幅広い癌種においてT細胞療法を効果的に展開するための重要なステップである。
<関連情報>
- https://pratt.duke.edu/news/master-regulator-of-the-dark-genome-greatly-improves-cancer-t-cell-therapy/
- https://www.nature.com/articles/s41588-023-01554-0
ヒトCD8+T細胞機能の転写およびエピジェネティック制御因子を直交CRISPRスクリーニングにより同定する Transcriptional and epigenetic regulators of human CD8+T cell function identified through orthogonal CRISPR screens
Sean R. McCutcheon,Adam M. Swartz,Michael C. Brown,Alejandro Barrera,Christian McRoberts Amador,Keith Siklenka,Lucas Humayun,Maria A. ter Weele,James M. Isaacs,Timothy E. Reddy,Andrew S. Allen,Smita K. Nair,Scott J. Antonia & Charles A. Gersbach
Nature Genetics Published:09 November 2023
DOI:https://doi.org/10.1038/s41588-023-01554-0
Abstract
Clinical response to adoptive T cell therapies is associated with the transcriptional and epigenetic state of the cell product. Thus, discovery of regulators of T cell gene networks and their corresponding phenotypes has potential to improve T cell therapies. Here we developed pooled, epigenetic CRISPR screening approaches to systematically profile the effects of activating or repressing 120 transcriptional and epigenetic regulators on human CD8+ T cell state. We found that BATF3 overexpression promoted specific features of memory T cells and attenuated gene programs associated with cytotoxicity, regulatory T cell function, and exhaustion. Upon chronic antigen stimulation, BATF3 overexpression countered phenotypic and epigenetic signatures of T cell exhaustion. Moreover, BATF3 enhanced the potency of CAR T cells in both in vitro and in vivo tumor models and programmed a transcriptional profile that correlates with positive clinical response to adoptive T cell therapy. Finally, we performed CRISPR knockout screens that defined cofactors and downstream mediators of the BATF3 gene network.
