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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 5

Costimulation maintains CD62L+ NKTs and prevents exhaustion.

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Costimulation maintains CD62L+ NKTs and prevents exhaustion.
(A) NKTs we...
(A) NKTs were sorted into CD62L+ and CD62L– subsets and stimulated and examined for expression of 4-1BB and OX40 by FACS before and 3 days after stimulation with αGalCer. Shown are plots from a representative of 4 donors. (B) CD62L+ NKTs were stimulated on plates coated with the indicated agonistic mAbs. Shown is mean ± SD (n = 4) of fold change in absolute NKT number on day 7 after stimulation compared with day 0. (C) CD62L+ NKTs were stimulated as in B and analyzed for CD62L expression (black) versus isotype control (gray) on day 7. Shown are representative overlay histograms (left panel) and mean ± SD of percent CD62L+ cells, n = 4. (D) CD62L+ NKTs were stimulated as in B and analyzed for the expression of PD-1 (black) versus isotype control (gray) on day 12. Shown are representative overlay histograms (left panel) and mean ± SD of percent PD-1+ cells. *P < 0.05, **P < 0.01, ***P < 0.001, 1-way ANOVA.
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