title: Exosomal evasion of humoral immunotherapy in aggressive B-cell lymphoma modulated by ATP-binding cassette transporter A3.
abstract: Targeting the surface of malignant cells has evolved into a cornerstone in cancer therapy, paradigmatically introduced by the success of humoral immunotherapy against CD20 in malignant lymphoma. However, tumor cell susceptibility to immunochemotherapy varies, with mostly a fatal outcome in cases of resistant disease. Here, we show that lymphoma exosomes shield target cells from antibody attack and that exosome biogenesis is modulated by the lysosome-related organelle-associated ATP-binding cassette (ABC) transporter A3 (ABCA3). B-cell lymphoma cells released exosomes that carried CD20, bound therapeutic anti-CD20 antibodies, consumed complement, and protected target cells from antibody attack. ABCA3, previously shown to mediate resistance to chemotherapy, was critical for the amounts of exosomes released, and both pharmacological blockade and the silencing of ABCA3 enhanced susceptibility of target cells to antibody-mediated lysis. Mechanisms of cancer cell resistance to drugs and antibodies are linked in an ABCA3-dependent pathway of exosome secretion.
authors.affiliation: Department of Hematology and Oncology, Georg-August-University, D-37075 Goettingen, Germany.
authors.forename: Thiha
authors.initials: T
authors.lastname: Aung
authors.forename: Bjoern
authors.initials: B
authors.lastname: Chapuy
authors.forename: Daniel
authors.initials: D
authors.lastname: Vogel
authors.forename: Dirk
authors.initials: D
authors.lastname: Wenzel
authors.forename: Martin
authors.initials: M
authors.lastname: Oppermann
authors.forename: Marlen
authors.initials: M
authors.lastname: Lahmann
authors.forename: Toni
authors.initials: T
authors.lastname: Weinhage
authors.forename: Kerstin
authors.initials: K
authors.lastname: Menck
authors.forename: Timo
authors.initials: T
authors.lastname: Hupfeld
authors.forename: Raphael
authors.initials: R
authors.lastname: Koch
authors.forename: Lorenz
authors.initials: L
authors.lastname: Trümper
authors.forename: Gerald G
authors.initials: GG
authors.lastname: Wulf
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000276:immunology*; D000042:Absorption; D058846:Antibodies, Monoclonal, Murine-Derived / Q000494:pharmacology; D000912:Antibodies, Neoplasm / Q000276:immunology; D018951:Antigens, CD20 / Q000276:immunology; D002460:Cell Line; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D055354:Exosomes / Q000187:drug effects / Q000276:immunology*; D020868:Gene Silencing / Q000187:drug effects; D006801:Humans; D057131:Immune Evasion / Q000187:drug effects / Q000276:immunology*; D056724:Immunity, Humoral / Q000187:drug effects / Q000276:immunology*; D007167:Immunotherapy; D016393:Lymphoma, B-Cell / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D000069283:Rituximab
chemical_list: C441524:ABCA3 protein, human; D018528:ATP-Binding Cassette Transporters; D058846:Antibodies, Monoclonal, Murine-Derived; D000912:Antibodies, Neoplasm; D018951:Antigens, CD20; D000069283:Rituximab