title: Transgene-enforced co-stimulation of CD4+ T cells leads to enhanced and sustained anti-tumor effector functioning.
abstract: Background The role of co-stimulation in CD4+ T cell activation by professional APC is well established, while less is known of the role co-stimulation plays when CD4+ T cells interact directly with tumor cells. Methods Through genetic engineering of human CD4+ T cells, we tested the hypothesis that integration of co-stimulatory signaling domains within a tumor-targeting chimeric Ag receptor (CAR), the IL-13Ralpha2-specific IL-13-zetakine (IL13zeta), would enhance CD4+ T cell mediated responses against tumors that fail to express ligands for co-stimulatory receptors. Results Compared with CD3zeta-mediated activation alone, CD4+ effector T cells expressing the IL13-CD28-41BBzeta CAR exhibited augmented/sustained MAPK and AKT activity, up-regulated Th1 cytokine production, and enhanced cytolytic potency against tumor targets. Moreover, upon recursive stimulation with tumor, the IL13-CD28-41BBzeta+ cells retained/recycled their lytic function, whereas IL-13zeta+ CD4+ cells became anergic/exhausted. These in vitro observations correlated with enhanced in vivo control of established orthotopic CNS glioma xenografts in immunodeficient mice mediated by adoptively transferred ex vivo-expanded CD4+ T cells expressing the co-stimulatory CAR. Discussion Together these studies demonstrate the importance of integrating co-stimulation with CD3zeta signaling events to activate fully CD4+ anti-tumor effector cells for sustained function in the tumor microenvironment.
authors.affiliation: Division of Cancer Immunotherapeutics & Tumor Immunology, City of Hope National Medical Center, Duarte, California 91010-3000, USA.
authors.forename: L
authors.initials: L
authors.lastname: Chang
authors.forename: W C
authors.initials: WC
authors.lastname: Chang
authors.forename: G
authors.initials: G
authors.lastname: McNamara
authors.forename: B
authors.initials: B
authors.lastname: Aguilar
authors.forename: J R
authors.initials: JR
authors.lastname: Ostberg
authors.forename: M C
authors.initials: MC
authors.lastname: Jensen
mesh_terms: D000818:Animals; D018106:CD28 Antigens / Q000276:immunology; D017252:CD3 Complex / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D003602:Cytotoxicity, Immunologic; D005910:Glioma / Q000276:immunology / Q000628:therapy; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology; D016219:Immunotherapy, Adoptive; D018793:Interleukin-13 / Q000276:immunology; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009369:Neoplasms / Q000276:immunology / Q000628:therapy; D017434:Protein Structure, Tertiary; D011993:Recombinant Fusion Proteins / Q000276:immunology; D015398:Signal Transduction; D019076:Transgenes / Q000276:immunology; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000276:immunology
chemical_list: D018106:CD28 Antigens; D017252:CD3 Complex; C121704:CD3 antigen, zeta chain; D007074:Immunoglobulin G; D018793:Interleukin-13; D011993:Recombinant Fusion Proteins; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9