| First Author | Mo F | Year | 2021 |
| Journal | Nature | Volume | 597 |
| Issue | 7877 | Pages | 544-548 |
| PubMed ID | 34526724 | Mgi Jnum | J:325906 |
| Mgi Id | MGI:7287794 | Doi | 10.1038/s41586-021-03861-0 |
| Citation | Mo F, et al. (2021) An engineered IL-2 partial agonist promotes CD8(+) T cell stemness. Nature 597(7877):544-548 |
| abstractText | 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. |
