title: Cooperative function of CCR7 and lymphotoxin in the formation of a lymphoma-permissive niche within murine secondary lymphoid organs.
abstract: Lymphoma cell survival and progression are putatively dependent on a specific microanatomic localization within secondary lymphoid organs. Despite compelling data correlating homeostatic chemokine receptor expression and human lymphoma pathogenesis, genetic models that either mimic lymphoma dissemination or dissect a crosstalk of lymphoma and stromal cells are missing. Applying the genetically tractable Eμ-Myc transgenic mouse model, we show that the chemokine receptor CCR7 regulates Eμ-Myc lymphoma homing to lymph nodes and distinctive microanatomic sites of the spleen. CCR7-controlled access of lymphoma cells to the splenic T-cell zone led to a significant survival advantage compared with CCR7-deficient lymphoma cells, which were excluded from this zone. Within the niche, lymphoma cells stimulated a reciprocal cross-talk with gp38(+) fibroblastic reticular cells. This reciprocal cooperation program was mediated by lymphoma B cell-presented lymphotoxin, which acted on lymphotoxin-β-receptor-bearing stromal cells followed by alteration of stromal cellular composition. Cross-talk inhibition by lymphotoxin-α deletion and using a lymphotoxin-β receptor-immunoglobulin fusion protein impaired lymphoma growth. Thus, abrogation of CCR7-governed migration and of sustained lymphotoxin signaling could provide new targets in lymphoma therapy.
authors.affiliation: Department of Hematology, Oncology and Tumorimmunology, Max-Delbrück-Center for Molecular Medicine, Berlin, Germany. arehm@mdc-berlin.de
authors.forename: Armin
authors.initials: A
authors.lastname: Rehm
authors.forename: Angela
authors.initials: A
authors.lastname: Mensen
authors.forename: Kristina
authors.initials: K
authors.lastname: Schradi
authors.forename: Kerstin
authors.initials: K
authors.lastname: Gerlach
authors.forename: Stefanie
authors.initials: S
authors.lastname: Wittstock
authors.forename: Susann
authors.initials: S
authors.lastname: Winter
authors.forename: Gilbert
authors.initials: G
authors.lastname: Büchner
authors.forename: Bernd
authors.initials: B
authors.lastname: Dörken
authors.forename: Martin
authors.initials: M
authors.lastname: Lipp
authors.forename: Uta E
authors.initials: UE
authors.lastname: Höpken
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D002465:Cell Movement; D002469:Cell Separation; D018450:Disease Progression; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008221:Lymphoid Tissue / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D016393:Lymphoma, B-Cell / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D008233:Lymphotoxin-alpha / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D020239:Receptor Cross-Talk / Q000502:physiology; D054400:Receptors, CCR7 / Q000276:immunology / Q000378:metabolism*; D016201:Receptors, Lymphocyte Homing / Q000276:immunology / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection; D059016:Tumor Microenvironment / Q000502:physiology*
chemical_list: D008233:Lymphotoxin-alpha; D054400:Receptors, CCR7; D016201:Receptors, Lymphocyte Homing