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The STING agonist IMSA101 enhances chimeric antigen receptor T cell function by inducing IL-18 secretion

Author

Listed:
  • Ugur Uslu

    (University of Pennsylvania Perelman School of Medicine
    Parker Institute for Cancer Immunotherapy at University of Pennsylvania)

  • Lijun Sun

    (ImmuneSensor Therapeutics)

  • Sofia Castelli

    (University of Pennsylvania Perelman School of Medicine
    Parker Institute for Cancer Immunotherapy at University of Pennsylvania)

  • Amanda V. Finck

    (University of Pennsylvania Perelman School of Medicine
    Parker Institute for Cancer Immunotherapy at University of Pennsylvania)

  • Charles-Antoine Assenmacher

    (University of Pennsylvania)

  • Regina M. Young

    (University of Pennsylvania Perelman School of Medicine
    Parker Institute for Cancer Immunotherapy at University of Pennsylvania)

  • Zhijian J. Chen

    (University of Texas Southwestern Medical Center
    University of Texas Southwestern Medical Center
    Howard Hughes Medical Institute)

  • Carl H. June

    (University of Pennsylvania Perelman School of Medicine
    Parker Institute for Cancer Immunotherapy at University of Pennsylvania)

Abstract

As a strategy to improve the therapeutic success of chimeric antigen receptor T cells (CART) directed against solid tumors, we here test the combinatorial use of CART and IMSA101, a newly developed stimulator of interferon genes (STING) agonist. In two syngeneic tumor models, improved overall survival is observed when mice are treated with intratumorally administered IMSA101 in addition to intravenous CART infusion. Transcriptomic analyses of CART isolated from tumors show elevated T cell activation, as well as upregulated cytokine pathway signatures, in particular IL-18, in the combination treatment group. Also, higher levels of IL-18 in serum and tumor are detected with IMSA101 treatment. Consistent with this, the use of IL-18 receptor negative CART impair anti-tumor responses in mice receiving combination treatment. In summary, we find that IMSA101 enhances CART function which is facilitated through STING agonist-induced IL-18 secretion.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-47692-9
    DOI: 10.1038/s41467-024-47692-9
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