title: Stromal interferon-γ signaling and cross-presentation are required to eliminate antigen-loss variants of B cell lymphomas in mice.
abstract: To study mechanisms of T cell-mediated rejection of B cell lymphomas, we developed a murine lymphoma model wherein three potential rejection antigens, human c-MYC, chicken ovalbumin (OVA), and GFP are expressed. After transfer into wild-type mice 60-70% of systemically growing lymphomas expressing all three antigens were rejected; lymphomas expressing only human c-MYC protein were not rejected. OVA expressing lymphomas were infiltrated by T cells, showed MHC class I and II upregulation, and lost antigen expression, indicating immune escape. In contrast to wild-type recipients, 80-100% of STAT1-, IFN-γ-, or IFN-γ receptor-deficient recipients died of lymphoma, indicating that host IFN-γ signaling is critical for rejection. Lymphomas arising in IFN-γ- and IFN-γ-receptor-deficient mice had invariably lost antigen expression, suggesting that poor overall survival of these recipients was due to inefficient elimination of antigen-negative lymphoma variants. Antigen-dependent eradication of lymphoma cells in wild-type animals was dependent on cross-presentation of antigen by cells of the tumor stroma. These findings provide first evidence for an important role of the tumor stroma in T cell-mediated control of hematologic neoplasias and highlight the importance of incorporating stroma-targeting strategies into future immunotherapeutic approaches.
authors.affiliation: Department of Immunology, Charité Berlin, Berlin, Germany. armin.gerbitz@uk-erlangen.de
authors.forename: Armin
authors.initials: A
authors.lastname: Gerbitz
authors.forename: Madhusudhanan
authors.initials: M
authors.lastname: Sukumar
authors.forename: Florian
authors.initials: F
authors.lastname: Helm
authors.forename: Andrea
authors.initials: A
authors.lastname: Wilke
authors.forename: Christian
authors.initials: C
authors.lastname: Friese
authors.forename: Cornelia
authors.initials: C
authors.lastname: Fahrenwaldt
authors.forename: Frank M
authors.initials: FM
authors.lastname: Lehmann
authors.forename: Christoph
authors.initials: C
authors.lastname: Loddenkemper
authors.forename: Thomas
authors.initials: T
authors.lastname: Kammertoens
authors.forename: Josef
authors.initials: J
authors.lastname: Mautner
authors.forename: Clemens A
authors.initials: CA
authors.lastname: Schmitt
authors.forename: Thomas
authors.initials: T
authors.lastname: Blankenstein
authors.forename: Georg W
authors.initials: GW
authors.lastname: Bornkamm
mesh_terms: D000818:Animals; D000941:Antigens / Q000235:genetics / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D002645:Chickens; D015972:Gene Expression Regulation, Neoplastic; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000276:immunology; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology*; D016393:Lymphoma, B-Cell / Q000235:genetics / Q000276:immunology* / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D010047:Ovalbumin / Q000235:genetics / Q000276:immunology; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction
chemical_list: D000941:Antigens; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D049452:Green Fluorescent Proteins; D007371:Interferon-gamma; D010047:Ovalbumin