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

Fei Mo, Zhiya Yu, Peng Li, Jangsuk Oh, Rosanne Spolski, Liang Zhao, Caleb R. Glassman, Tori N. Yamamoto, Yun Chen, Filip M. Golebiowski, Dalton Hermans, Sonia Majri-Morrison, Lora K. Picton, Wei Liao, Min Ren, Xiaoxuan Zhuang, Suman Mitra, Jian-Xin Lin, Luca Gattinoni, Jonathan D. Powell, Nicholas P. Restifo (), K. Christopher Garcia () and Warren J. Leonard ()
Additional contact information
Fei Mo: National Institutes of Health
Zhiya Yu: National Cancer Institute
Peng Li: National Institutes of Health
Jangsuk Oh: National Institutes of Health
Rosanne Spolski: National Institutes of Health
Liang Zhao: Johns Hopkins University School of Medicine
Caleb R. Glassman: Stanford University School of Medicine
Tori N. Yamamoto: National Cancer Institute
Yun Chen: National Institutes of Health
Filip M. Golebiowski: National Institutes of Health
Dalton Hermans: National Institutes of Health
Sonia Majri-Morrison: Stanford University School of Medicine
Lora K. Picton: Stanford University School of Medicine
Wei Liao: National Institutes of Health
Min Ren: National Institutes of Health
Xiaoxuan Zhuang: National Institutes of Health
Suman Mitra: National Institutes of Health
Jian-Xin Lin: National Institutes of Health
Luca Gattinoni: National Cancer Institute
Jonathan D. Powell: Johns Hopkins University School of Medicine
Nicholas P. Restifo: National Cancer Institute
K. Christopher Garcia: Stanford University School of Medicine
Warren J. Leonard: National Institutes of Health

Nature, 2021, vol. 597, issue 7877, 544-548

Abstract: 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 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 cells4,5 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.

Date: 2021
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DOI: 10.1038/s41586-021-03861-0

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