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

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 a...

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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
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creator Gerbitz, Armin
Sukumar, Madhusudhanan
Helm, Florian
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Friese, Christian
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Kammertoens, Thomas
Mautner, Josef
Schmitt, Clemens A
Blankenstein, Thomas
Bornkamm, Georg W
description 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.
doi_str_mv 10.1371/journal.pone.0034552
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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.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>22479645</pmid><doi>10.1371/journal.pone.0034552</doi><oa>free_for_read</oa></addata></record>
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identifier ISSN: 1932-6203
ispartof PloS one, 2012-03, Vol.7 (3), p.e34552-e34552
issn 1932-6203
1932-6203
language eng
recordid cdi_plos_journals_1324394928
source Open Access: PubMed Central; Publicly Available Content Database
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
title Stromal interferon-γ signaling and cross-presentation are required to eliminate antigen-loss variants of B cell lymphomas in mice
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