title: Disruption of T cell regulatory pathways is necessary for immunotherapeutic cure of T cell acute lymphoblastic leukemia in mice.
abstract: Acute lymphoblastic leukemia (ALL) is the most common cancer in children. In recent years, the outcome has been globally improved by current therapies, but it remains poor in patients with high, persistent residual disease following the first course of chemotherapy, prompting evaluation of the possible beneficial effects of immunotherapy protocols. In this study, we hypothesized that the disruption of two immunoregulatory pathways controlling the auto-reactive T cell response might synergize with dendritic cell-based immunotherapy of the disease, which is considered to be poorly immunogenic. In this study, we used TAL1xLMO1 leukemia cells adoptively transferred in mice, to generate murine leukemia with poorly immunogenic cells as a model for human T-ALL. Subsequently, these animals were treated with several different immunotherapeutic protocols. We compared the efficiency of a classical, dendritic cell-based immunotherapy (injection of dendritic cells loaded with tumor-derived antigenic products), to a combined treatment associating injection of antigen-loaded dendritic cells and disruption of the two immunoregulatory pathways: CD25+ suppressive T cells and cytotoxic T lymphocyte-associated antigens (CTLA-4). We show that this combined treatment resulted in cure, concomitantly with in vivo generation of immune memory, and TNF-alpha secretion. This study demonstrates that the disruption of these two immunoregulatory pathways synergized with immunostimulation by dendritic cells loaded with tumor-derived antigens, and paves the way for the testing of this combination in clinical trials.
authors.affiliation: Unité U728 INSERM-Laboratoire de Pathologie Université Paris VII, Hôpital Saint-Louis--Institut Universitaire d'Hématologie, 1 avenue Claude-Vellefaux, 75475 Paris Cedex 10, France.
authors.forename: S
authors.initials: S
authors.lastname: Fiorentino
authors.forename: M
authors.initials: M
authors.lastname: Chopin
authors.forename: H
authors.initials: H
authors.lastname: Dastot
authors.forename: N
authors.initials: N
authors.lastname: Boissel
authors.forename: M
authors.initials: M
authors.lastname: Reboul
authors.forename: L
authors.initials: L
authors.lastname: Legrès
authors.forename: A
authors.initials: A
authors.lastname: Janin
authors.forename: P
authors.initials: P
authors.lastname: Aplan
authors.forename: F
authors.initials: F
authors.lastname: Sigaux
authors.forename: Armelle
authors.initials: A
authors.lastname: Regnault
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D000951:Antigens, Neoplasm / Q000008:administration & dosage; D060908:CTLA-4 Antigen; D045744:Cell Line, Tumor; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism / Q000637:transplantation; D004195:Disease Models, Animal; D007156:Immunologic Memory; D016219:Immunotherapy, Adoptive; D053645:Interleukin-2 Receptor alpha Subunit / Q000096:biosynthesis; D008212:Lymphocyte Depletion; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000276:immunology* / Q000378:metabolism / Q000628:therapy*; D015398:Signal Transduction / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D015703:Antigens, CD; D000951:Antigens, Neoplasm; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C556707:Ctla4 protein, mouse; D053645:Interleukin-2 Receptor alpha Subunit; D014409:Tumor Necrosis Factor-alpha