title: Tumor cells in multiple myeloma patients inhibit myeloma-reactive T cells through carcinoembryonic antigen-related cell adhesion molecule-6.
abstract: Although functionally competent cytotoxic, T cells are frequently observed in malignant diseases, they possess little ability to react against tumor cells. This phenomenon is particularly apparent in multiple myeloma. We here demonstrate that cytotoxic T cells reacted against myeloma antigens when presented by autologous dendritic cells, but not by myeloma cells. We further show by gene expression profiling and flow cytometry that, similar to many other malignant tumors, freshly isolated myeloma cells expressed several carcinoembryonic antigen-related cell adhesion molecules (CEACAMs) at varying proportions. Binding and crosslinking of CEACAM-6 by cytotoxic T cells inhibited their activation and resulted in T-cell unresponsiveness. Blocking of CEACAM-6 on the surface of myeloma cells by specific monoclonal antibodies or CEACAM-6 gene knock down by short interfering RNA restored T-cell reactivity against malignant plasma cells. These findings suggest that CEACAM-6 plays an important role in the regulation of CD8+ T-cell responses against multiple myeloma; therefore, therapeutic targeting of CEACAM-6 may be a promising strategy to improve myeloma immunotherapy.
authors.affiliation: Department of Hematology/Oncology, University Hospital of Heidelberg, Heidelberg, Germany;
authors.forename: Mathias
authors.initials: M
authors.lastname: Witzens-Harig
authors.forename: Dirk
authors.initials: D
authors.lastname: Hose
authors.forename: Simone
authors.initials: S
authors.lastname: Jünger
authors.forename: Christina
authors.initials: C
authors.lastname: Pfirschke
authors.forename: Nisit
authors.initials: N
authors.lastname: Khandelwal
authors.forename: Ludmila
authors.initials: L
authors.lastname: Umansky
authors.forename: Anja
authors.initials: A
authors.lastname: Seckinger
authors.forename: Heinke
authors.initials: H
authors.lastname: Conrad
authors.forename: Bettina
authors.initials: B
authors.lastname: Brackertz
authors.forename: Thierry
authors.initials: T
authors.lastname: Rème
authors.forename: Brigitte
authors.initials: B
authors.lastname: Gueckel
authors.forename: Tobias
authors.initials: T
authors.lastname: Meißner
authors.forename: Michael
authors.initials: M
authors.lastname: Hundemer
authors.forename: Anthony D
authors.initials: AD
authors.lastname: Ho
authors.forename: Jean-Francois
authors.initials: JF
authors.lastname: Rossi
authors.forename: Kai
authors.initials: K
authors.lastname: Neben
authors.forename: Helga
authors.initials: H
authors.lastname: Bernhard
authors.forename: Hartmut
authors.initials: H
authors.lastname: Goldschmidt
authors.forename: Bernard
authors.initials: B
authors.lastname: Klein
authors.forename: Philipp
authors.initials: P
authors.lastname: Beckhove
mesh_terms: D015703:Antigens, CD / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D018920:Coculture Techniques; D003602:Cytotoxicity, Immunologic / Q000235:genetics / Q000276:immunology; D058851:GPI-Linked Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D061986:MCF-7 Cells; D009101:Multiple Myeloma / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D010950:Plasma Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000378:metabolism; D014407:Tumor Cells, Cultured; D020298:U937 Cells
chemical_list: D015703:Antigens, CD; C504117:CEACAM6 protein, human; D015815:Cell Adhesion Molecules; D058851:GPI-Linked Proteins; D034741:RNA, Small Interfering