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CD62L+ NKT cells have prolonged persistence and antitumor activity in vivo
Gengwen Tian, … , Laurence J. Cooper, Leonid S. Metelitsa
Gengwen Tian, … , Laurence J. Cooper, Leonid S. Metelitsa
Published May 16, 2016
Citation Information: J Clin Invest. 2016;126(6):2341-2355. https://doi.org/10.1172/JCI83476.
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Research Article Oncology

CD62L+ NKT cells have prolonged persistence and antitumor activity in vivo

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Abstract

Vα24-invariant natural killer T cells (NKTs) localize to tumors and have inherent antitumor properties, making them attractive chimeric antigen receptor (CAR) carriers for redirected cancer immunotherapy. However, clinical application of CAR-NKTs has been impeded, as mechanisms responsible for NKT expansion and the in vivo persistence of these cells are unknown. Here, we demonstrated that antigen-induced expansion of primary NKTs in vitro associates with the accumulation of a CD62L+ subset and exhaustion of CD62L– cells. Only CD62L+ NKTs survived and proliferated in response to secondary stimulation. When transferred to immune-deficient NSG mice, CD62L+ NKTs persisted 5 times longer than CD62L– NKTs. Moreover, CD62L+ cells transduced with a CD19-specific CAR achieved sustained tumor regression in a B cell lymphoma model. Proliferating CD62L+ cells downregulated or maintained CD62L expression when activated via T cell receptor alone or in combination with costimulatory receptors. We generated HLAnull K562 cell clones that were engineered to express CD1d and costimulatory ligands. Clone B-8-2 (HLAnullCD1dmedCD86high4-1BBLmedOX40Lhigh) induced the highest rates of NKT expansion and CD62L expression. B-8-2–expanded CAR-NKTs exhibited prolonged in vivo persistence and superior therapeutic activities in models of lymphoma and neuroblastoma. Therefore, we have identified CD62L as a marker of a distinct NKT subset endowed with high proliferative potential and have developed artificial antigen-presenting cells that generate CD62L-enriched NKTs for effective cancer immunotherapy.

Authors

Gengwen Tian, Amy N. Courtney, Bipulendu Jena, Andras Heczey, Daofeng Liu, Ekaterina Marinova, Linjie Guo, Xin Xu, Hiroki Torikai, Qianxing Mo, Gianpietro Dotti, Laurence J. Cooper, Leonid S. Metelitsa

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Figure 1

Accumulation of CD62L+ subset in culture after in vitro antigenic stimulation of primary NKTs.

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Accumulation of CD62L+ subset in culture after in vitro antigenic stimul...
(A) CD62L expression was examined by FACS in primary NKTs from freshly isolated PBMCs (day 0) and 12 days after stimulation with αGalCer and in vitro expansion in culture (n = 10). (B) Kinetics of CD62L expression in NKTs at the indicated intervals after primary stimulation (as in A) from individual donors (n = 10). (C) Expression of PD-1, TIM-3, and LAG-3 on NKT surface was measured by FACS on days 0 and 12 (top panel). Representative plots from 1 of 4 donors (middle panel) or mean ± SD of mean fluorescence intensity (MFI) for all donors (n = 4, bottom panel). (D) On day 12 after primary stimulation, NKTs were magnetically sorted into CD62L+ and CD62L– subsets followed by RNA isolation and gene expression analysis using Human Immunology Panel version 2 and nCounter Analysis System (NanoString). The heat map shows the log2 fold changes (CD62+/CD62L–) of genes with P values less than 0.02 and average fold change greater than 2. Data were generated from 6 NKT donors (12 paired samples). **P < 0.01, ***P < 0.001, paired t test.
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