title: CD62L+ NKT cells have prolonged persistence and antitumor activity in vivo.
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.forename: Gengwen
authors.initials: G
authors.lastname: Tian
authors.forename: Amy N
authors.initials: AN
authors.lastname: Courtney
authors.forename: Bipulendu
authors.initials: B
authors.lastname: Jena
authors.forename: Andras
authors.initials: A
authors.lastname: Heczey
authors.forename: Daofeng
authors.initials: D
authors.lastname: Liu
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Marinova
authors.forename: Linjie
authors.initials: L
authors.lastname: Guo
authors.forename: Xin
authors.initials: X
authors.lastname: Xu
authors.forename: Hiroki
authors.initials: H
authors.lastname: Torikai
authors.forename: Qianxing
authors.initials: Q
authors.lastname: Mo
authors.forename: Gianpietro
authors.initials: G
authors.lastname: Dotti
authors.forename: Laurence J
authors.initials: LJ
authors.lastname: Cooper
authors.forename: Leonid S
authors.initials: LS
authors.lastname: Metelitsa
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D003602:Cytotoxicity, Immunologic; D006801:Humans; D016219:Immunotherapy, Adoptive; D019041:L-Selectin / Q000378:metabolism*; D008213:Lymphocyte Activation; D016393:Lymphoma, B-Cell / Q000276:immunology / Q000628:therapy; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D055611:Natural Killer T-Cells / Q000145:classification / Q000276:immunology*; D009447:Neuroblastoma / Q000276:immunology / Q000628:therapy; D011946:Receptors, Antigen / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000276:immunology; D023041:Xenograft Model Antitumor Assays
chemical_list: D016207:Cytokines; D011946:Receptors, Antigen; D011993:Recombinant Fusion Proteins; C546935:SELL protein, human; D019041:L-Selectin