An engineered IL-2 partial agonist promotes CD8(+) T cell stemness

Article

关键词: CHAIN CYTOKINES IL-2;    EFFECTOR DIFFERENTIATION;    MEMORY;    INTERLEUKIN-2;    EXHAUSTION;    EXPRESSION;    RECEPTOR;    TIM-3;    PD-1;    IMMUNOTHERAPY;   

DOI  :  10.1038/s41586-021-03861-0

来源: SCIE

【 摘 要 】

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.

【 授权许可】

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