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

Author

Listed:
  • Elisa Landoni

    (University of North Carolina)

  • Mark G. Woodcock

    (University of North Carolina
    University of North Carolina)

  • Gabriel Barragan

    (Baylor College of Medicine)

  • Gabriele Casirati

    (Dana-Farber/Boston Children’s Cancer and Blood Disorder Center
    Harvard Medical School)

  • Vincenzo Cinella

    (Dana-Farber/Boston Children’s Cancer and Blood Disorder Center
    Harvard Medical School)

  • Simone Stucchi

    (University of North Carolina)

  • Leah M. Flick

    (University of North Carolina)

  • Tracy A. Withers

    (University of North Carolina)

  • Hanna Hudson

    (University of North Carolina)

  • Giulia Casorati

    (Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute)

  • Paolo Dellabona

    (Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute)

  • Pietro Genovese

    (Dana-Farber/Boston Children’s Cancer and Blood Disorder Center
    Harvard Medical School)

  • Barbara Savoldo

    (University of North Carolina
    University of North Carolina)

  • Leonid S. Metelitsa

    (Baylor College of Medicine)

  • Gianpietro Dotti

    (University of North Carolina
    University of North Carolina)

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.

Suggested Citation

  • 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 & Piet, 2024. "IL-12 reprograms CAR-expressing natural killer T cells to long-lived Th1-polarized cells with potent antitumor activity," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-023-44310-y
    DOI: 10.1038/s41467-023-44310-y
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    References listed on IDEAS

    as
    1. J. Joseph Melenhorst & Gregory M. Chen & Meng Wang & David L. Porter & Changya Chen & McKensie A. Collins & Peng Gao & Shovik Bandyopadhyay & Hongxing Sun & Ziran Zhao & Stefan Lundh & Iulian Pruteanu, 2022. "Decade-long leukaemia remissions with persistence of CD4+ CAR T cells," Nature, Nature, vol. 602(7897), pages 503-509, February.
    2. J. Joseph Melenhorst & Gregory M. Chen & Meng Wang & David L. Porter & Changya Chen & McKensie A. Collins & Peng Gao & Shovik Bandyopadhyay & Hongxing Sun & Ziran Zhao & Stefan Lundh & Iulian Pruteanu, 2022. "Author Correction: Decade-long leukaemia remissions with persistence of CD4+ CAR T cells," Nature, Nature, vol. 612(7941), pages 22-22, December.
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