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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 6

Generation of functional characterization of costimulatory aAPCs for NKT expansion.

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Generation of functional characterization of costimulatory aAPCs for NKT...
(A) CD1d+HLAnull K562 clones were transduced with the costimulatory molecules, indicated in Table 1, irradiated, and pulsed with αGalCer to stimulate NKTs. NKTs were counted on day 12 after stimulation. Shown is mean ± SD (n = 3) of fold increase in NKT absolute number compared with day 0 for each aAPC clone from a representative of 8 experiments performed in triplicates. All groups were compared with the group in which NKTs were stimulated with autologous PBMCs, 1-way ANOVA. (B) After primary expansion with αGalCer-pulsed autologous PBMCs, NKTs from 4 donors were restimulated with αGalCer-pulsed B-8-2 clone followed by culture with IL-2. The absolute count of NKTs was performed at the indicated time intervals (n = 4). (C) After primary expansion with αGalCer-pulsed autologous PBMCs, NKTs were restimulated with autologous PBMCs or with B-8-2. CD62L expression was analyzed by FACS on day 12 using NKTs from 3 donors. P < 0.001, paired t test.

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

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