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

Nature. 2021 Sep;597(7877):544-548. doi: 10.1038/s41586-021-03861-0. Epub 2021 Sep 15.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD8-Positive T-Lymphocytes / cytology*
  • CD8-Positive T-Lymphocytes / drug effects*
  • CD8-Positive T-Lymphocytes / immunology
  • Cell Differentiation / drug effects*
  • Drug Partial Agonism*
  • Interleukin-2 / agonists*
  • Interleukin-2 / analogs & derivatives*
  • Interleukin-2 / chemistry
  • Interleukin-2 / genetics
  • Melanoma / metabolism
  • Mice
  • Mitochondria / drug effects
  • Mutant Proteins / chemistry
  • Mutant Proteins / genetics
  • Mutant Proteins / pharmacology*
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / metabolism
  • Receptors, Antigen, T-Cell / genetics
  • Receptors, Antigen, T-Cell / metabolism
  • STAT5 Transcription Factor / metabolism
  • Stem Cells / cytology
  • Stem Cells / drug effects*
  • T Cell Transcription Factor 1 / metabolism
  • Translational Research, Biomedical

Substances

  • Interleukin-2
  • Mutant Proteins
  • Receptors, Antigen, T-Cell
  • STAT5 Transcription Factor
  • T Cell Transcription Factor 1
  • TCF7 protein, human