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.