GSE138698
An engineered IL-2 partial agonist promotes CD8+ T cell stemness
Adoptive transfer of antigen-specific T cells represents a major advance in cancer immunotherapy, with robust clinical outcomes in some patients . Both the number of transferred T cells and their differentiation state are critical determinants of effective responses. 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 and lower therapeutic efficacy, whereas maintenance of a more stem-cell-like state before adoptive transfer is beneficial. Here we show that H9T, an engineered interleukin-2 partial agonist, promotes the expansion of T cells without driving terminal differentiation. H9T led to altered STAT5 signalling and mediated distinctive downstream transcriptional, epigenetic and metabolic programs. In addition, H9T 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 models of melanoma and acute lymphoblastic leukaemia. Thus, using engineered cytokine variants with distinctive properties is a promising strategy, with broad translational potential. Overall design: ChIP-Seq, RNA-Seq and ATAC-Seq analyses using TCR pre-activated CD8+ T cells that were expanded with either no cytokine, or with IL-2, H9 or H9T.