Mo, Fei and Yu, Zhiya and Li, Peng and Oh, Jangsuk and Spolski, Rosanne and Zhao, Liang and Glassman, Caleb R. and Yamamoto, Tori N. and Chen, Yun and Golebiowski, Filip M. and Hermans, Dalton and Majri-Morrison, Sonia and Picton, Lora K. and Liao, Wei and Ren, Min and Zhuang, Xiaoxuan and Mitra, Suman and Lin, Jian-Xin and Gattinoni, Luca and Powell, Jonathan D. and Restifo, Nicholas P. and Garcia, K. Christopher and Leonard, Warren J. (2021) An engineered IL-2 partial agonist promotes CD8(+) T cell stemness. NATURE, 597 (7877). 544-+. ISSN 0028-0836, 1476-4687
Full text not available from this repository. (Request a copy)Abstract
Adoptive transfer of antigen-specific T cells represents a major advance in cancer immunotherapy, with robust clinical outcomes in some patients(1). Both the number of transferred T cells and their differentiation state are critical determinants of effective responses(2,3). T cells can be expanded with T cell receptor (TCR)-mediated stimulation and interleukin-2, but this can lead to differentiation into effector T cells(4,5) and lower therapeutic efficacy(6), whereas maintenance of a more stem-cell-like state before adoptive transfer is beneficial(7). Here we show that H9T, an engineered interleukin-2 partial agonist, promotes the expansion of CD8(+) T cells without driving terminal differentiation. H9T led to altered STAT5 signalling and mediated distinctive downstream transcriptional, epigenetic and metabolic programs. In addition, H9T treatment sustained the expression of T cell transcription factor 1 (TCF-1) and promoted mitochondrial fitness, thereby facilitating the maintenance of a stem-cell-like state. Moreover, TCR-transgenic and chimeric antigen receptor-modified CD8(+) T cells that were expanded with H9T showed robust anti-tumour activity in vivo in mouse models of melanoma and acute lymphoblastic leukaemia. Thus, engineering cytokine variants with distinctive properties is a promising strategy for creating new molecules with translational potential.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | CHAIN CYTOKINES IL-2; EFFECTOR DIFFERENTIATION; MEMORY; INTERLEUKIN-2; EXHAUSTION; EXPRESSION; RECEPTOR; TIM-3; PD-1; IMMUNOTHERAPY; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Zentren des Universitätsklinikums Regensburg > Regensburger Centrum für Interventionelle Immunologie (RCI) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 21 Sep 2022 08:19 |
| Last Modified: | 21 Sep 2022 08:19 |
| URI: | https://pred.uni-regensburg.de/id/eprint/47818 |
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