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Potentiating adoptive cell therapy using synthetic IL-9 receptors

Author

Listed:
  • Anusha Kalbasi

    (University of California, Los Angeles
    Parker Institute for Cancer Immunotherapy)

  • Mikko Siurala

    (Parker Institute for Cancer Immunotherapy
    University of Pennsylvania)

  • Leon L. Su

    (Stanford University School of Medicine)

  • Mito Tariveranmoshabad

    (University of California, Los Angeles)

  • Lora K. Picton

    (Stanford University School of Medicine)

  • Pranali Ravikumar

    (University of Pennsylvania)

  • Peng Li

    (National Heart, Lung, and Blood Institute, National Institutes of Health)

  • Jian-Xin Lin

    (National Heart, Lung, and Blood Institute, National Institutes of Health)

  • Helena Escuin-Ordinas

    (University of California, Los Angeles)

  • Tong Da

    (University of Pennsylvania)

  • Sarah V. Kremer

    (University of California, Los Angeles)

  • Amy L. Sun

    (University of California, Los Angeles)

  • Sofia Castelli

    (University of Pennsylvania)

  • Sangya Agarwal

    (University of Pennsylvania)

  • John Scholler

    (University of Pennsylvania)

  • Decheng Song

    (University of Pennsylvania)

  • Philipp C. Rommel

    (University of Pennsylvania)

  • Enrico Radaelli

    (University of Pennsylvania)

  • Regina M. Young

    (University of Pennsylvania)

  • Warren J. Leonard

    (National Heart, Lung, and Blood Institute, National Institutes of Health)

  • Antoni Ribas

    (Parker Institute for Cancer Immunotherapy
    University of California, Los Angeles)

  • Carl H. June

    (Parker Institute for Cancer Immunotherapy
    University of Pennsylvania)

  • K. Christopher Garcia

    (Parker Institute for Cancer Immunotherapy
    Stanford University School of Medicine
    Stanford University School of Medicine
    Stanford University School of Medicine)

Abstract

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.

Suggested Citation

  • Anusha Kalbasi & Mikko Siurala & Leon L. Su & Mito Tariveranmoshabad & Lora K. Picton & Pranali Ravikumar & Peng Li & Jian-Xin Lin & Helena Escuin-Ordinas & Tong Da & Sarah V. Kremer & Amy L. Sun & So, 2022. "Potentiating adoptive cell therapy using synthetic IL-9 receptors," Nature, Nature, vol. 607(7918), pages 360-365, July.
  • Handle: RePEc:nat:nature:v:607:y:2022:i:7918:d:10.1038_s41586-022-04801-2
    DOI: 10.1038/s41586-022-04801-2
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    Citations

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    Cited by:

    1. Anna-Maria Makri Pistikou & Glenn A. O. Cremers & Bryan L. Nathalia & Theodorus J. Meuleman & Bas W. A. Bögels & Bruno V. Eijkens & Anne Dreu & Maarten T. H. Bezembinder & Oscar M. J. A. Stassen & Car, 2023. "Engineering a scalable and orthogonal platform for synthetic communication in mammalian cells," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    2. Ugur Uslu & Lijun Sun & Sofia Castelli & Amanda V. Finck & Charles-Antoine Assenmacher & Regina M. Young & Zhijian J. Chen & Carl H. June, 2024. "The STING agonist IMSA101 enhances chimeric antigen receptor T cell function by inducing IL-18 secretion," Nature Communications, Nature, vol. 15(1), pages 1-16, December.

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