Language

English

Publication Date

2-3-2023

Journal

Cancer Immunology Research

DOI

10.1158/2326-6066.CIR-22-0333

PMID

36484736

PMCID

PMC9898189

PubMedCentral® Posted Date

8-3-2023

PubMedCentral® Full Text Version

Author MSS

Abstract

Vα24-invariant natural killer T cells (NKT) possess innate antitumor properties that can be exploited for cancer immunotherapy. We have shown previously that the CD62L+ central memory-like subset of these cells drives the in vivo antitumor activity of NKTs, but molecular mediators of NKT central memory differentiation remain unknown. Here, we demonstrate that relative to CD62L- cells, CD62L+ NKTs express a higher level of the gene encoding the Wnt/β-catenin transcription factor lymphoid enhancer binding factor 1 (LEF1) and maintain active Wnt/β-catenin signaling. CRISPR/Cas9-mediated LEF1 knockout reduced CD62L+ frequency after antigenic stimulation, whereas Wnt/β-catenin activator Wnt3a ligand increased CD62L+ frequency. LEF1 overexpression promoted NKT expansion and limited exhaustion following serial tumor challenge and was sufficient to induce a central memory-like transcriptional program in NKTs. In mice, NKTs expressing a GD2-specific chimeric-antigen receptor (CAR) with LEF1 demonstrated superior control of neuroblastoma xenograft tumors compared with control CAR-NKTs. These results identify LEF1 as a transcriptional activator of the NKT central memory program and advance development of NKT cell-based immunotherapy. See related Spotlight by Van Kaer, p. 144.

Keywords

Humans, Animals, Mice, Natural Killer T-Cells, beta Catenin, Lymphoid Enhancer-Binding Factor 1, Receptors, Chimeric Antigen, Lymphocyte Activation

Published Open-Access

yes

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