Stromal interferon-γ signaling and cross-presentation are required to eliminate antigen-loss variants of B cell lymphomas in mice

• Published in: PloS one 2012-03, Vol.7 (3), p.e34552-e34552
• Main Authors: Gerbitz, Armin, Sukumar, Madhusudhanan, Helm, Florian, Wilke, Andrea, Friese, Christian, Fahrenwaldt, Cornelia, Lehmann, Frank M, Loddenkemper, Christoph, Kammertoens, Thomas, Mautner, Josef, Schmitt, Clemens A, Blankenstein, Thomas, Bornkamm, Georg W
• Format: Article
• Language: English
• Subjects: Animals; Antigen presentation; Antigens; Antigens - genetics; Antigens - immunology; B-cell lymphoma; B-Lymphocytes - immunology; B-Lymphocytes - metabolism; B-Lymphocytes - pathology; Biology; c-Myc protein; Cancer therapies; Chemotherapy; Chickens; Dendritic cells; Gene Expression Regulation, Neoplastic; Genes; Genetics; Green Fluorescent Proteins - genetics; Green Fluorescent Proteins - immunology; Hematology; Humans; Immune system; Immunology; Immunotherapy; Interferon; Interferon-gamma - immunology; Leukemia; Lymphocytes; Lymphocytes B; Lymphocytes T; Lymphoma; Lymphoma, B-Cell - genetics; Lymphoma, B-Cell - immunology; Lymphoma, B-Cell - pathology; Major histocompatibility complex; Medicine; Mice; Mice, Inbred C57BL; Molecular biology; Mutation; Myc protein; Oncology; Ovalbumin; Ovalbumin - genetics; Ovalbumin - immunology; Proteins; Proto-Oncogene Proteins c-myc - genetics; Proto-Oncogene Proteins c-myc - immunology; Rejection; Senescence; Signal Transduction; Signaling; Stat1 protein; Stroma; Transgenic animals; Transplants & implants; Tumors; γ-Interferon
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0034552

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.