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 and Gianpietro Dotti ()
Additional contact information
Elisa Landoni: University of North Carolina
Mark G. Woodcock: University of North Carolina
Gabriel Barragan: Baylor College of Medicine
Gabriele Casirati: Dana-Farber/Boston Children’s Cancer and Blood Disorder Center
Vincenzo Cinella: Dana-Farber/Boston Children’s Cancer and Blood Disorder Center
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
Barbara Savoldo: University of North Carolina
Leonid S. Metelitsa: Baylor College of Medicine
Gianpietro Dotti: University of North Carolina

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-023-44310-y

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