IL-18R-dependent and independent pathways account for IL-18-enhanced antitumor ability of CAR-T cells

FASEB J. 2020 Jan;34(1):1768-1782. doi: 10.1096/fj.201901809R. Epub 2019 Dec 6.


Interleukin-18 (IL-18) has been demonstrated to augment the antitumor capacity of chimeric antigen receptor-T cells (CAR-T) but the underlying mechanisms are largely unknown. Here we explored the effects and mechanisms of exogenous IL-18 on the antitumor response of CAR-T cells. IL-18 boosted the cytotoxicity of human epidermal growth factor receptor-2 (HER2)-specific CAR-T cells ex vivo and enhanced the antitumor efficacy of the CAR-T cells in immunodeficient mice, moreover, IL-18 improved the antitumor capacity of OVA-specific T cells in immunocompetent mice, indicating the universal enhancing function of IL-18 for adoptive cell therapy. To address the roles of IL-18 receptor (IL-18R) in the enhancing function, we evaluated the effects of IL-18R knockout (IL-18R-/-) condition in immunocompetent host and CAR-T cells on the IL-18-enhanced antitumor activities. Interestingly, IL-18 persisted to improve the antitumor ability of IL-18R intact CAR-T cells in IL-18R-/- mice. For IL-18R-/- CAR-T cells, however, IL-18 still holds the enhancing ability to boost the antitumor efficacy in IL-18R-/- mice, albeit the ex vivo tumor-killing ability was lower than that of IL-18R intact CAR-T cells, indicating that IL-18R-independent pathway is involved in the enhancement. Furthermore, tagged IL-18 binded to the membrane of IL-18R-/- splenic and lymph node cells and IL-18R intact and IL-18R-/- CAR-T cells showed distinct transcriptomic profiles when stimulated by IL-18. These data demonstrate that IL-18R-independent pathways contribute to functions of IL-18.

Keywords: CAR‐T; IL‐18; IL‐18 receptor; cancer immunotherapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / metabolism*
  • Cell Line
  • Female
  • HEK293 Cells
  • Humans
  • Immunotherapy, Adoptive / methods
  • Interleukin-18 / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred NOD
  • Mice, SCID
  • Receptors, Antigen, T-Cell / metabolism*
  • Receptors, Interleukin-18 / metabolism*
  • Signal Transduction / physiology*
  • T-Lymphocytes / metabolism*
  • Xenograft Model Antitumor Assays / methods


  • Antineoplastic Agents
  • IL18 protein, human
  • Interleukin-18
  • Receptors, Antigen, T-Cell
  • Receptors, Interleukin-18