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

Mo F, Yu Z, Li P, Oh J, Spolski R, Zhao L, Glassman CR, Yamamoto TN, Chen Y, Golebiowski FM, Hermans D, Majri-Morrison S, Picton LK, Liao W, Ren M, Zhuang X, Mitra S, Lin JX, Gattinoni L, Powell JD, Restifo NP, Garcia KC, Leonard WJ (2021)

Publication Type: Journal article

Publication year: 2021

Journal

Nature Nature Research

Book Volume: 597

Pages Range: 544-548

Journal Issue: 7877

DOI: 10.1038/s41586-021-03861-0

Abstract

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 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 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.

Involved external institutions

US National Institutes of Health (NIH)

United States (USA) (US) Stanford University

United States (USA) (US) National Cancer Institute (NCI)

United States (USA) (US) Johns Hopkins University (JHU)

United States (USA) (US) National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK / NIDDKD)

United States (USA) (US)

How to cite

APA:

Mo, F., Yu, Z., Li, P., Oh, J., Spolski, R., Zhao, L.,... Leonard, W.J. (2021). An engineered IL-2 partial agonist promotes CD8+ T cell stemness. Nature, 597(7877), 544-548. https://doi.org/10.1038/s41586-021-03861-0

MLA:

Mo, Fei, et al. "An engineered IL-2 partial agonist promotes CD8+ T cell stemness." Nature 597.7877 (2021): 544-548.

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