title: T cell-encoded CD80 and 4-1BBL induce auto- and transcostimulation, resulting in potent tumor rejection.
abstract: To reject tumors, T cells must overcome poor tumor immunogenicity and an adverse tumor microenvironment. Providing agonistic costimulatory signals to tumor-infiltrating T cells to augment T cell function remains a challenge for the implementation of safe and effective immunotherapy. We hypothesized that T cells overexpressing selected costimulatory ligands could serve as cellular vehicles mediating powerful, yet constrained, anatomically targeted costimulation. Here, we show that primary human T cells expressing CD80 and 4-1BB ligand (4-1BBL) vigorously respond to tumor cells lacking costimulatory ligands and provoke potent rejection of large, systemic tumors in immunodeficient mice. In addition to showing costimulation of bystander T cells (transcostimulation), we show the effect of CD80 and 4-1BBL binding to their respective receptors in the immunological synapse of isolated single cells (autocostimulation). This new strategy of endowing T cells with constitutively expressed costimulatory ligands could be extended to other ligand-receptor pairs and used to enhance any targeted adoptive transfer therapy.
authors.affiliation: Center for Cell Engineering, Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center (MSKCC), New York, New York 10021, USA.
authors.forename: Matthias T
authors.initials: MT
authors.lastname: Stephan
authors.forename: Vladimir
authors.initials: V
authors.lastname: Ponomarev
authors.forename: Renier J
authors.initials: RJ
authors.lastname: Brentjens
authors.forename: Alex H
authors.initials: AH
authors.lastname: Chang
authors.forename: Konstantin V
authors.initials: KV
authors.lastname: Dobrenkov
authors.forename: Glenn
authors.initials: G
authors.lastname: Heller
authors.forename: Michel
authors.initials: M
authors.lastname: Sadelain
mesh_terms: D053330:4-1BB Ligand / Q000378:metabolism*; D019264:Adoptive Transfer; D000818:Animals; D000938:Antigen-Presenting Cells; D018122:B7-1 Antigen / Q000378:metabolism*; D045744:Cell Line, Tumor; D006801:Humans; D007107:Immune System; D051379:Mice; D016513:Mice, SCID; D018613:Microscopy, Confocal; D009369:Neoplasms / Q000276:immunology* / Q000378:metabolism; D011485:Protein Binding; D012190:Retroviridae / Q000378:metabolism; D013601:T-Lymphocytes / Q000378:metabolism
chemical_list: D053330:4-1BB Ligand; D018122:B7-1 Antigen