title: 4-1BB ligand modulates direct and Rituximab-induced NK-cell reactivity in chronic lymphocytic leukemia.
abstract: NK cells play an important role in tumor immunosurveillance and largely contribute to the therapeutic success of anti-tumor antibodies like Rituximab. Here, we studied the role of the TNF family member 4-1BB ligand (4-1BBL) during the interaction of NK cells with chronic lymphocytic leukemia (CLL) cells. 4-1BBL was highly expressed on patient B-CLL cells in all 56 investigated cases. Signaling via 4-1BBL following interaction with 4-1BB, which was detected on NK cells of CLL patients but not healthy individuals, led to the release of immunoregulatory cytokines including TNF by CLL cells. CLL patient sera contained elevated levels of TNF and induced 4-1BB upregulation on NK cells, which in turn impaired direct and Rituximab-induced NK-cell reactivity against 4-1BBL-expressing targets. NK-cell reactivity was not only enhanced by blocking the interaction of NK cell-expressed 4-1BB with 4-1BBL expressed by CLL cells, but also by preventing 4-1BB upregulation on NK cells via neutralization of TNF in patient serum with Infliximab. Our data indicate that 4-1BBL mediates NK-cell immunosubversion in CLL, and thus might contribute to the reportedly compromised efficacy of Rituximab to induce NK-cell reactivity in the disease, and that TNF neutralization may serve to enhance the efficacy of Rituximab treatment in CLL.
authors.affiliation: Department of Hematology, Eberhard Karls University of Tuebingen, Tuebingen, Germany.
authors.forename: Corina
authors.initials: C
authors.lastname: Buechele
authors.forename: Tina
authors.initials: T
authors.lastname: Baessler
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Schmiedel
authors.forename: Carla E
authors.initials: CE
authors.lastname: Schumacher
authors.forename: Ludger
authors.initials: L
authors.lastname: Grosse-Hovest
authors.forename: Kilian
authors.initials: K
authors.lastname: Rittig
authors.forename: Helmut R
authors.initials: HR
authors.lastname: Salih
mesh_terms: D053330:4-1BB Ligand / Q000235:genetics / Q000276:immunology*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D058846:Antibodies, Monoclonal, Murine-Derived / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D003601:Cytotoxicity Tests, Immunologic; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D012313:RNA / Q000737:chemistry / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000069283:Rituximab; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000276:immunology
chemical_list: D053330:4-1BB Ligand; D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents; D014409:Tumor Necrosis Factor-alpha; D000069283:Rituximab; D012313:RNA