title: Analysis and characterization of antitumor T-cell response after administration of dendritic cells loaded with allogeneic tumor lysate to metastatic melanoma patients.
abstract: The primary goal of cancer vaccines is to induce CD8+ T cells specific for tumor-associated antigens (TAA) but the characterization of these cells has been difficult because of the low sensitivity of ex vivo assays. Here, we focused on TAA-specific CD8+ T-cell responses in melanoma patients after vaccination with autologous dendritic cells loaded with lysates derived from allogeneic tumor-cell lines (Lysate-DC). Out of 40 patients treated, 16 patients developed immune response to tumor-cell lysate and/or CD8+ T cells specific for differentiation and cancer-testis antigens. TAA-specific CD8+ T-cell responses were detected by interferon (IFN)-gamma enzyme-linked immunospot after in vitro sensitization and were, either transient during the treatment period or delayed, that is, observed after completion of all vaccinations. We could not correlate these immune responses to clinical data as none of the patients achieved an overall objective response according to Response Evaluation Criteria in Solid Tumors criteria. Three patients were reported as stable disease and 10 patients presented evidence of antitumor activity. We found that TAA-specific T cells characterized in 4 patients produced perforin ex vivo, but no IFN-gamma in enzyme-linked immunospot. Differential expression of IFN-gamma and perforin was also observed for viral-specific T cells. Altogether, our results show that Lysate-DC therapy elicited tumor-specific CD8+ T cells nonlimited to human leukocyte antigen-A2+ patients, with some T cells secreting perforin ex vivo and IFN-gamma only after restimulation. The differential expression of perforin and IFN-gamma by antitumor and antiviral CD8+ T cells supports that the sole use of IFN-gamma production to monitor T cells overlooks functional T-cell subpopulations triggered by vaccines.
authors.affiliation: IDM, Hopital Européen Georges Pompidou, Unité d'Immunologie Biologique, EA 4054 Université Paris, France.
authors.forename: Nadege
authors.initials: N
authors.lastname: Bercovici
authors.forename: Nacilla
authors.initials: N
authors.lastname: Haicheur
authors.forename: Severine
authors.initials: S
authors.lastname: Massicard
authors.forename: Frederique
authors.initials: F
authors.lastname: Vernel-Pauillac
authors.forename: Olivier
authors.initials: O
authors.lastname: Adotevi
authors.forename: Didier
authors.initials: D
authors.lastname: Landais
authors.forename: Isabelle
authors.initials: I
authors.lastname: Gorin
authors.forename: Caroline
authors.initials: C
authors.lastname: Robert
authors.forename: H Miles
authors.initials: HM
authors.lastname: Prince
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Grob
authors.forename: Marie Thérèse
authors.initials: MT
authors.lastname: Leccia
authors.forename: Thierry
authors.initials: T
authors.lastname: Lesimple
authors.forename: John
authors.initials: J
authors.lastname: Wijdenes
authors.forename: Jacques
authors.initials: J
authors.lastname: Bartholeyns
authors.forename: Wolf H
authors.initials: WH
authors.lastname: Fridman
authors.forename: Margarita
authors.initials: M
authors.lastname: Salcedo
authors.forename: Estelle
authors.initials: E
authors.lastname: Ferries
authors.forename: Eric
authors.initials: E
authors.lastname: Tartour
mesh_terms: D000951:Antigens, Neoplasm / Q000276:immunology*; D000956:Antigens, Viral / Q000276:immunology; D019496:Cancer Vaccines / Q000276:immunology / Q000627:therapeutic use*; D003713:Dendritic Cells / Q000276:immunology / Q000637:transplantation*; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D007700:Kinetics; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D008545:Melanoma / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D009362:Neoplasm Metastasis; D054353:Perforin / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: D000951:Antigens, Neoplasm; D000956:Antigens, Viral; D019496:Cancer Vaccines; D018984:Epitopes, T-Lymphocyte; D054353:Perforin; D007371:Interferon-gamma