| Autor: |
Mo, Fei, Yu, Zhiya, Li, Peng, Oh, Jangsuk, Spolski, Rosanne, Zhao, Liang, Glassman, Caleb R., Yamamoto, Tori N., Chen, Yun, Golebiowski, Filip M., Hermans, Dalton, Majri-Morrison, Sonia, Picton, Lora K., Liao, Wei, Ren, Min, Zhuang, Xiaoxuan, Mitra, Suman, Lin, Jian-Xin, Gattinoni, Luca, Powell, Jonathan D., Restifo, Nicholas P., Garcia, K. Christopher, Leonard, Warren J. |
| Zdroj: |
Nature; 20210101, Issue: Preprints p1-5, 5p |
| Abstrakt: |
Adoptive transfer of antigen-specific T cells represents a major advance in cancer immunotherapy, with robust clinical outcomes in some patients1. Both the number of transferred T cells and their differentiation state are critical determinants of effective responses2,3. T cells can be expanded with T cell receptor (TCR)-mediated stimulation and interleukin-2, but this can lead to differentiation into effector T cells4,5and lower therapeutic efficacy6, whereas maintenance of a more stem-cell-like state before adoptive transfer is beneficial7. 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. |
| Databáze: |
Supplemental Index |
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