Language
English
Publication Date
1-2-2024
Journal
Nature Communications
DOI
10.1038/s41467-023-44310-y
PMID
38167707
PMCID
PMC1076226
PubMedCentral® Posted Date
1-2-2024
PubMedCentral® Full Text Version
Post-print
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.
Keywords
Humans, Receptors, Chimeric Antigen, Interleukin-12, Natural Killer T-Cells, Cytotoxicity, Immunologic, Lymphocyte Activation, Cancer immunotherapy, Interleukins, Tumour immunology
Published Open-Access
yes
Recommended Citation
Landoni, Elisa; Woodcock, Mark G; Barragan, Gabriel; et al., "Il-12 Reprograms Car-Expressing Natural Killer T Cells to Long-Lived Th1-Polarized Cells With Potent Antitumor Activity" (2024). Faculty, Staff and Students Publications. 6320.
https://digitalcommons.library.tmc.edu/baylor_docs/6320