Language
English
Publication Date
11-1-2024
Journal
Nature Cancer
DOI
10.1038/s43018-024-00830-0
PMID
39354225
PMCID
PMC12002392
PubMedCentral® Posted Date
4-16-2025
PubMedCentral® Full Text Version
Author MSS
Abstract
Human natural killer T (NKT) cells have been proposed as a promising cell platform for chimeric antigen receptor (CAR) therapy in solid tumors. Here we generated murine CAR-NKT cells and compared them with CAR-T cells in immune-competent mice. Both CAR-NKT cells and CAR-T cells showed similar antitumor effects in vitro, but CAR-NKT cells showed superior antitumor activity in vivo via CD1d-dependent immune responses in the tumor microenvironment. Specifically, we show that CAR-NKT cells eliminate CD1d-expressing M2-like macrophages. In addition, CAR-NKT cells promote epitope spreading and activation of endogenous T cell responses against tumor-associated neoantigens. Finally, we observed that CAR-NKT cells can co-express PD1 and TIM3 and show an exhaustion phenotype in a model of high tumor burden. PD1 blockade as well as vaccination augmented the antitumor activity of CAR-NKT cells. In summary, our results demonstrate the multimodal function of CAR-NKT cells in solid tumors, further supporting the rationale for developing CAR-NKT therapies in the clinic.
Keywords
Animals, Mice, Natural Killer T-Cells, Receptors, Chimeric Antigen, Immunotherapy, Adoptive, Antigens, CD1d, Tumor Microenvironment, Programmed Cell Death 1 Receptor, Humans, Cell Line, Tumor, Hepatitis A Virus Cellular Receptor 2, Macrophages, Mice, Inbred C57BL, Female
Published Open-Access
yes
Recommended Citation
Zhou, Xin; Wang, Ying; Dou, Zhangqi; et al., "Car-Redirected Natural Killer T Cells Demonstrate Superior Antitumor Activity to Car-T Cells Through Multimodal CD1d-Dependent Mechanisms" (2024). Faculty, Staff and Students Publications. 6332.
https://digitalcommons.library.tmc.edu/baylor_docs/6332