title: Upregulation of adhesion molecules on leukemia targets improves the efficacy of cytotoxic T cells transduced with chimeric anti-CD19 receptor.
abstract: T lymphocytes engineered to express chimeric antigen receptors (CARs) interact directly with cell surface molecules, bypassing MHC antigen presentation dependence. We generated human anti-CD19ζ CAR cytotoxic T lymphocytes and cytokine-induced killer cells and studied their sensitivity to the expression of adhesion molecules for the killing of primary B-lineage acute lymphoblastic leukemia (B-ALL) targets. Despite a very low basal expression of surface adhesion molecules, B-ALL blasts were lysed by the anti-CD19ζ-CAR transduced effectors as expected. We next investigated the regulatory role of adhesion molecules during CAR-mediated cytolysis. The blocking of these accessory molecules strongly limited the chimeric effector's cytotoxicity. Thereafter, B-ALL cells surface adhesion molecule level expression was induced by IFN-γ or by the combined use of CD40L and IL-4 and the cells were submitted to anti-CD19ζ-CAR transduced effectors lysis. Upregulation of adhesion molecules expression by blasts potentiated their killing. The improved cytotoxicity observed was dependent on target surface expression of adhesion molecules, particularly CD54. Taken together, these results indicate that adhesion molecules, and principally CD54, are involved in the efficiency of recognition by effector chimeric ζ. These observations have potential implications for the design of immunotherapy treatment approaches for hematological malignancies and tumors based on the adoption of CAR effector cells.
authors.affiliation: Etablissement Français du Sang, 29 av du Maquis du Grésivaudan, BP35, 38701 La Tronche, France. david.laurin@efs.sante.fr
authors.forename: David
authors.initials: D
authors.lastname: Laurin
authors.forename: Virna
authors.initials: V
authors.lastname: Marin
authors.forename: Ettore
authors.initials: E
authors.lastname: Biagi
authors.forename: Irene
authors.initials: I
authors.lastname: Pizzitola
authors.forename: Valentina
authors.initials: V
authors.lastname: Agostoni
authors.forename: Géraldine
authors.initials: G
authors.lastname: Gallot
authors.forename: Henri
authors.initials: H
authors.lastname: Vié
authors.forename: Marie Christine
authors.initials: MC
authors.lastname: Jacob
authors.forename: Laurence
authors.initials: L
authors.lastname: Chaperot
authors.forename: Caroline
authors.initials: C
authors.lastname: Aspord
authors.forename: Joël
authors.initials: J
authors.lastname: Plumas
mesh_terms: D018941:Antigens, CD19 / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology; D001854:Bone Marrow Cells / Q000276:immunology; D002051:Burkitt Lymphoma / Q000276:immunology; D019013:CD40 Antigens / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000096:biosynthesis / Q000276:immunology; D045744:Cell Line, Tumor; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism*; D007371:Interferon-gamma / Q000276:immunology; D015847:Interleukin-4 / Q000378:metabolism; D019169:Jurkat Cells; D015448:Leukemia, B-Cell / Q000276:immunology* / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000276:immunology; D034622:RNA Interference; D034741:RNA, Small Interfering; D011947:Receptors, Antigen, B-Cell / Q000096:biosynthesis / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D015854:Up-Regulation
chemical_list: D018941:Antigens, CD19; D019013:CD40 Antigens; D015815:Cell Adhesion Molecules; D034741:RNA, Small Interfering; D011947:Receptors, Antigen, B-Cell; D018799:Intercellular Adhesion Molecule-1; D015847:Interleukin-4; D007371:Interferon-gamma