Landoni et al. showed that IL-12-transduced human blood NKT cells were Th1 polarized and polyfunctional, overexpressed activation and memory (CD62L) markers, and had autocrine/ paracrine IL-12 activity and increased proliferation upon stimulation. IL-12 stimulated de novo CD62L expression and proliferative responses in CD62L+ and CD62L- untransduced NKT. IL-12+ NKT cells engrafted in mice retained CD62L expression and had greater expansion and persistence than controls. IL-12 co-expression, either soluble or membrane-bound, boosted CAR-NKT cell CD62L expression, Th1 polarization, and antitumor activity in vitro and in leukemia and neuroblastoma mouse models.
Contributed by Paula Hochman
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.
Author Info: (1) Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA. (2) Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hil
Author Info: (1) Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA. (2) Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA. Division of Oncology, Department of Medicine, University of North Carolina, Chapel Hill, NC, USA. (3) Center for Advanced Innate Cell Therapy, Texas Children's Cancer Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA. (4) Dana-Farber/Boston Children's Cancer and Blood Disorder Center, Boston, USA. Harvard Medical School, Boston, USA. (5) Dana-Farber/Boston Children's Cancer and Blood Disorder Center, Boston, USA. Harvard Medical School, Boston, USA. (6) Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA. (7) Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA. (8) Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA. (9) Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA. (10) Experimental Immunology Unit, Division of Immunology, Transplantation and Infectious Diseases, San Raffaele Scientific Institute, Milan, Italy. (11) Experimental Immunology Unit, Division of Immunology, Transplantation and Infectious Diseases, San Raffaele Scientific Institute, Milan, Italy. (12) Dana-Farber/Boston Children's Cancer and Blood Disorder Center, Boston, USA. Harvard Medical School, Boston, USA. (13) Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA. Department of Pediatrics, University of North Carolina, Chapel Hill, NC, USA. (14) Center for Advanced Innate Cell Therapy, Texas Children's Cancer Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA. (15) Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA. gdotti@med.unc.edu. Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC, USA. gdotti@med.unc.edu.
