Interleukin-23 engineering improves CAR T cell function in solid tumors

Nat Biotechnol. 2020 Apr;38(4):448-459. doi: 10.1038/s41587-019-0398-2. Epub 2020 Feb 3.


Cytokines that stimulate T cell proliferation, such as interleukin (IL)-15, have been explored as a means of boosting the antitumor activity of chimeric antigen receptor (CAR) T cells. However, constitutive cytokine signaling in T cells and activation of bystander cells may cause toxicity. IL-23 is a two-subunit cytokine known to promote proliferation of memory T cells and T helper type 17 cells. We found that, upon T cell antigen receptor (TCR) stimulation, T cells upregulated the IL-23 receptor and the IL-23α p19 subunit, but not the p40 subunit. We engineered expression of the p40 subunit in T cells (p40-Td cells) and obtained selective proliferative activity in activated T cells via autocrine IL-23 signaling. In comparison to CAR T cells, p40-Td CAR T cells showed improved antitumor capacity in vitro, with increased granzyme B and decreased PD-1 expression. In two xenograft and two syngeneic solid tumor mouse models, p40-Td CAR T cells showed superior efficacy in comparison to CAR T cells and attenuated side effects in comparison to CAR T cells expressing IL-18 or IL-15.

Publication types

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

MeSH terms

  • Animals
  • Cell Hypoxia / genetics
  • Cell Line, Tumor
  • Cell Proliferation
  • Humans
  • Immunotherapy, Adoptive / methods*
  • Interleukin-12 Subunit p40 / genetics
  • Interleukin-12 Subunit p40 / metabolism
  • Interleukin-23 / genetics
  • Interleukin-23 / metabolism*
  • Lymphocyte Activation
  • Mice
  • Neoplasms / immunology
  • Neoplasms / therapy*
  • Receptors, Antigen, T-Cell / genetics
  • Receptors, Antigen, T-Cell / metabolism
  • Receptors, Chimeric Antigen / genetics
  • Receptors, Chimeric Antigen / metabolism
  • Receptors, Interleukin / genetics
  • Receptors, Interleukin / metabolism
  • STAT3 Transcription Factor / metabolism
  • Signal Transduction / genetics
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / metabolism
  • Xenograft Model Antitumor Assays


  • IL23R protein, human
  • Interleukin-12 Subunit p40
  • Interleukin-23
  • Receptors, Antigen, T-Cell
  • Receptors, Chimeric Antigen
  • Receptors, Interleukin
  • STAT3 Transcription Factor
  • STAT3 protein, human