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- Title
CD62L+ NKT cells have prolonged persistence and antitumor activity in vivo.
- Authors
Gengwen Tian; Courtney, Amy N.; Jena, Bipulendu; Heczey, Andras; Daofeng Liu; Marinova, Ekaterina; Linjie Guo; Xin Xu; Hiroki Torikai; Qianxing Mo; Dotti, Gianpietro; Cooper, Laurence J.; Metelitsa, Leonid S.; Tian, Gengwen; Liu, Daofeng; Guo, Linjie; Xu, Xin; Torikai, Hiroki; Mo, Qianxing
- 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.
- Subjects
T cells; TUMOR treatment; ANTIGEN receptors; IMMUNOTHERAPY; SPONTANEOUS cancer regression
- Publication
Journal of Clinical Investigation, 2016, Vol 126, Issue 6, p2341
- ISSN
0021-9738
- Publication type
journal article
- DOI
10.1172/JCI83476