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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 3

CD62L+ NKTs have superior survival and proliferative capacity upon secondary stimulation.

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CD62L+ NKTs have superior survival and proliferative capacity upon secon...
(A) CFSE-labeled NKTs were magnetically sorted into CD62L+ and CD62L– subsets as confirmed by post-sorting FACS (top plot) and stimulated with irradiated αGalCer-pulsed APCs. On day 3 after stimulation, staining for annexin V and 7-AAD was analyzed in NKTs by FACS after gating on CFSE+ events. Results are from a representative of 5 donors tested (middle panel). The corresponding bar graph (bottom panel) shows mean ± SD of percent annexin V+ NKTs on day 3 (n = 5). (B) Cell proliferation was assessed on day 6 after stimulation as measured by CFSE dilution. Results are from a representative of 5 donors tested (top panel) and mean ± SD of CFSE MFI for all donors (n = 5, bottom panel). (C) Total cell counts were performed at the indicated time intervals after NKT stimulation. Shown is mean ± SD (n = 3) viable cells for a representative donor (top panel) or fold change for each of 5 donors tested on day 6 after stimulation. **P < 0.01, ***P < 0.001, paired t test.

Copyright © 2022 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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