Potentiating adoptive cell therapy using synthetic IL-9 receptors

Nature. 2022 Jul;607(7918):360-365. doi: 10.1038/s41586-022-04801-2. Epub 2022 Jun 8.


Synthetic receptor signalling has the potential to endow adoptively transferred T cells with new functions that overcome major barriers in the treatment of solid tumours, including the need for conditioning chemotherapy1,2. Here we designed chimeric receptors that have an orthogonal IL-2 receptor extracellular domain (ECD) fused with the intracellular domain (ICD) of receptors for common γ-chain (γc) cytokines IL-4, IL-7, IL-9 and IL-21 such that the orthogonal IL-2 cytokine elicits the corresponding γc cytokine signal. Of these, T cells that signal through the chimeric orthogonal IL-2Rβ-ECD-IL-9R-ICD (o9R) are distinguished by the concomitant activation of STAT1, STAT3 and STAT5 and assume characteristics of stem cell memory and effector T cells. Compared to o2R T cells, o9R T cells have superior anti-tumour efficacy in two recalcitrant syngeneic mouse solid tumour models of melanoma and pancreatic cancer and are effective even in the absence of conditioning lymphodepletion. Therefore, by repurposing IL-9R signalling using a chimeric orthogonal cytokine receptor, T cells gain new functions, and this results in improved anti-tumour activity for hard-to-treat solid tumours.

Publication types

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

MeSH terms

  • Animals
  • Cell- and Tissue-Based Therapy* / methods
  • Immunotherapy, Adoptive* / methods
  • Interleukin Receptor Common gamma Subunit* / genetics
  • Interleukin Receptor Common gamma Subunit* / immunology
  • Interleukins / genetics
  • Interleukins / immunology
  • Melanoma / immunology
  • Mice
  • Neoplasms* / genetics
  • Neoplasms* / immunology
  • Pancreatic Neoplasms / immunology
  • Receptors, Interleukin-9* / genetics
  • Receptors, Interleukin-9* / immunology
  • Recombinant Fusion Proteins* / genetics
  • Recombinant Fusion Proteins* / immunology
  • STAT Transcription Factors / metabolism
  • T-Lymphocytes* / immunology
  • T-Lymphocytes* / metabolism


  • Interleukin Receptor Common gamma Subunit
  • Interleukins
  • Receptors, Interleukin-9
  • Recombinant Fusion Proteins
  • STAT Transcription Factors