Nature Communications (Jan 2024)

IL-12 reprograms CAR-expressing natural killer T cells to long-lived Th1-polarized cells with potent antitumor activity

  • Elisa Landoni,
  • Mark G. Woodcock,
  • Gabriel Barragan,
  • Gabriele Casirati,
  • Vincenzo Cinella,
  • Simone Stucchi,
  • Leah M. Flick,
  • Tracy A. Withers,
  • Hanna Hudson,
  • Giulia Casorati,
  • Paolo Dellabona,
  • Pietro Genovese,
  • Barbara Savoldo,
  • Leonid S. Metelitsa,
  • Gianpietro Dotti

DOI
https://doi.org/10.1038/s41467-023-44310-y
Journal volume & issue
Vol. 15, no. 1
pp. 1 – 16

Abstract

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Abstract Human natural killer T cells (NKTs) are innate-like T lymphocytes increasingly used for cancer immunotherapy. Here we show that human NKTs expressing the pro-inflammatory cytokine interleukin-12 (IL-12) undergo extensive and sustained molecular and functional reprogramming. Specifically, IL-12 instructs and maintains a Th1-polarization program in NKTs in vivo without causing their functional exhaustion. Furthermore, using CD62L as a marker of memory cells in human NKTs, we observe that IL-12 maintains long-term CD62L-expressing memory NKTs in vivo. Notably, IL-12 initiates a de novo programming of memory NKTs in CD62L-negative NKTs indicating that human NKTs circulating in the peripheral blood possess an intrinsic differentiation hierarchy, and that IL-12 plays a role in promoting their differentiation to long-lived Th1-polarized memory cells. Human NKTs engineered to co-express a Chimeric Antigen Receptor (CAR) coupled with the expression of IL-12 show enhanced antitumor activity in leukemia and neuroblastoma tumor models, persist long-term in vivo and conserve the molecular signature driven by the IL-12 expression. Thus IL-12 reveals an intrinsic plasticity of peripheral human NKTs that may play a crucial role in the development of cell therapeutics.