title: Ex vivo characterization of multiepitopic tumor-specific CD8 T cells in patients with chronic myeloid leukemia: implications for vaccine development and adoptive cellular immunotherapy.
abstract: Identification of tumor-associated Ags is a prerequisite for vaccine-based and adoptive immune therapies. Some tumor-associated Ags elicit specific CD8 T cells in patients with chronic myeloid leukemia (CML). Here, we characterized ex vivo responses of CD8 T cells from CML patients to extrajunction bcr-abl peptides and telomerase 540-548 hTert, PR1, and WT1 peptides. CML-specific CD8 T cells were present in most treated patients and were usually multiepitopic: WT1, hTert, PR1, and bcr74 tetramer(+) cells were detected in 85, 82, 67, and 61% of patients, respectively. The breadth and magnitude of these responses did not differ significantly according to treatment or disease status. CML-specific tetramer(+) CD8 T cells had a predominantly memory phenotype, an intermediate perforin content, and low intracellular IFN-gamma accumulation in the presence of the relevant peptide. However, in short-term culture with HLA-matched leukemia cells, the patients' memory T cells were specifically reactivated to become IFN-gamma-producing effector cells, suggesting that CD8 T cell precursors with lytic potential are present in vivo and can be activated by appropriate stimulation. In conclusion, this study shows that multiepitopic tumor-specific CD8 T cell responses occur naturally in most CML patients, opening the way to new strategies for enhancing anti-CML immunity, in particular in patients with minimal residual disease.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM) Equipe Avenir, Unité 561, Hôpital St-Vincent de Paul, Paris, France.
authors.forename: Monique
authors.initials: M
authors.lastname: Gannagé
authors.forename: Michal
authors.initials: M
authors.lastname: Abel
authors.forename: Anne-Sophie
authors.initials: AS
authors.lastname: Michallet
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Delluc
authors.forename: Marion
authors.initials: M
authors.lastname: Lambert
authors.forename: Stéphane
authors.initials: S
authors.lastname: Giraudier
authors.forename: Roland
authors.initials: R
authors.lastname: Kratzer
authors.forename: Gabriele
authors.initials: G
authors.lastname: Niedermann
authors.forename: Loredana
authors.initials: L
authors.lastname: Saveanu
authors.forename: François
authors.initials: F
authors.lastname: Guilhot
authors.forename: Luc
authors.initials: L
authors.lastname: Camoin
authors.forename: Bruno
authors.initials: B
authors.lastname: Varet
authors.forename: Agnès
authors.initials: A
authors.lastname: Buzyn
authors.forename: Sophie
authors.initials: S
authors.lastname: Caillat-Zucman
mesh_terms: D000951:Antigens, Neoplasm / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D019496:Cancer Vaccines / Q000276:immunology*; D004268:DNA-Binding Proteins / Q000276:immunology / Q000378:metabolism; D018984:Epitopes, T-Lymphocyte / Q000276:immunology* / Q000378:metabolism; D016044:Fusion Proteins, bcr-abl / Q000276:immunology / Q000378:metabolism; D015789:HLA-A2 Antigen / Q000378:metabolism; D006801:Humans; D007156:Immunologic Memory; D016130:Immunophenotyping; D016219:Immunotherapy, Adoptive / Q000379:methods; D007371:Interferon-gamma / Q000096:biosynthesis; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D018655:Lymphocyte Count; D053146:Myeloblastin; D010446:Peptide Fragments / Q000378:metabolism; D011485:Protein Binding / Q000276:immunology; D012697:Serine Endopeptidases / Q000276:immunology / Q000378:metabolism; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D019098:Telomerase / Q000276:immunology / Q000378:metabolism; D025721:WT1 Proteins / Q000276:immunology / Q000378:metabolism
chemical_list: D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D004268:DNA-Binding Proteins; D018984:Epitopes, T-Lymphocyte; D015789:HLA-A2 Antigen; D010446:Peptide Fragments; D025721:WT1 Proteins; D007371:Interferon-gamma; D016044:Fusion Proteins, bcr-abl; D019098:Telomerase; D012697:Serine Endopeptidases; D053146:Myeloblastin