title: Soluble ligands for NK cell receptors promote evasion of chronic lymphocytic leukemia cells from NK cell anti-tumor activity.
abstract: Natural killer (NK) cells are a major component of the anti-tumor immune response. NK cell dysfunctions have been reported in various hematologic malignancies, including chronic lymphocytic leukemia (CLL). Here we investigated the role of tumor cell-released soluble and exosomal ligands for NK cell receptors that modulate NK cell activity. Soluble CLL plasma factors suppressed NK cell cytotoxicity and down-regulated the surface receptors CD16 and CD56 on NK cells of healthy donors. The inhibition of NK cell cytotoxicity was attributed to the soluble ligand BAG6/BAT3 that engages the activating receptor NKp30 expressed on NK cells. Soluble BAG6 was detectable in the plasma of CLL patients, with the highest levels at the advanced disease stages. In contrast, NK cells were activated when BAG6 was presented on the surface of exosomes. The latter form was induced in non-CLL cells by cellular stress via an nSmase2-dependent pathway. Such cells were eliminated by lymphocytes in a xenograft tumor model in vivo. Here, exosomal BAG6 was essential for tumor cell killing because BAG6-deficient cells evaded immune detection. Taken together, the findings show that the dysregulated balance of exosomal vs soluble BAG6 expression may cause immune evasion of CLL cells.
authors.affiliation: Department I of Internal Medicine, University of Cologne, Cologne, Germany.
authors.forename: Katrin S
authors.initials: KS
authors.lastname: Reiners
authors.forename: Daniela
authors.initials: D
authors.lastname: Topolar
authors.forename: Alexander
authors.initials: A
authors.lastname: Henke
authors.forename: Venkateswara R
authors.initials: VR
authors.lastname: Simhadri
authors.forename: Jörg
authors.initials: J
authors.lastname: Kessler
authors.forename: Maike
authors.initials: M
authors.lastname: Sauer
authors.forename: Martina
authors.initials: M
authors.lastname: Bessler
authors.forename: Hinrich P
authors.initials: HP
authors.lastname: Hansen
authors.forename: Samir
authors.initials: S
authors.lastname: Tawadros
authors.forename: Marco
authors.initials: M
authors.lastname: Herling
authors.forename: Martin
authors.initials: M
authors.lastname: Krönke
authors.forename: Michael
authors.initials: M
authors.lastname: Hallek
authors.forename: Elke
authors.initials: E
authors.lastname: Pogge von Strandmann
mesh_terms: D000818:Animals; D019002:CD56 Antigen / Q000378:metabolism / Q000502:physiology; D002478:Cells, Cultured; D055354:Exosomes / Q000378:metabolism; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism / Q000502:physiology; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D008024:Ligands; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D051379:Mice; D016513:Mice, SCID; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D017452:Receptors, IgG / Q000378:metabolism / Q000502:physiology; D055607:Receptors, Natural Killer Cell / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012995:Solubility; D019139:Tumor Escape / Q000187:drug effects* / Q000235:genetics; D059016:Tumor Microenvironment / Q000235:genetics / Q000276:immunology
chemical_list: C092009:BAG6 protein, human; D019002:CD56 Antigen; D008024:Ligands; D018832:Molecular Chaperones; D017452:Receptors, IgG; D055607:Receptors, Natural Killer Cell