CD62L+ NKT cells have prolonged persistence and antitumor activity in vivo
| Autor: | Qianxing Mo, Leonid S. Metelitsa, Amy N. Courtney, Bipulendu Jena, Laurence J.N. Cooper, Linjie Guo, Xin Xu, Ekaterina Marinova, Andras Heczey, Daofeng Liu, Gianpietro Dotti, Gengwen Tian, Hiroki Torikai |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Cytotoxicity Immunologic Lymphoma B-Cell Cell Survival medicine.medical_treatment Recombinant Fusion Proteins Antigen-Presenting Cells chemical and pharmacologic phenomena Mice SCID Biology Lymphocyte Activation Immunotherapy Adoptive 03 medical and health sciences Mice Neuroblastoma Cancer immunotherapy Mice Inbred NOD Cell Line Tumor medicine Animals Humans L-Selectin Antigen-presenting cell Cells Cultured Cell Proliferation Mice Knockout T-cell receptor hemic and immune systems General Medicine Immunotherapy Natural killer T cell Xenograft Model Antitumor Assays Chimeric antigen receptor Receptors Antigen 030104 developmental biology CD1D Immunology biology.protein Cancer research Cytokines Natural Killer T-Cells Clone (B-cell biology) Research Article |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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