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

Authors

  • A. Gerbitz
  • M. Sukumar
  • F. Helm
  • A. Wilke
  • C. Friese
  • C. Fahrenwaldt
  • F.M. Lehmann
  • C. Loddenkemper
  • T. Kammertoens
  • J. Mautner
  • C.A. Schmitt
  • T. Blankenstein
  • G.W. Bornkamm

Journal

  • PLoS ONE

Citation

  • PLoS ONE 7 (3): e34552

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-{gamma}-, or IFN-{gamma} receptor-deficient recipients died of lymphoma, indicating that host IFN-{gamma} signaling is critical for rejection. Lymphomas arising in IFN-{gamma}- and IFN-{gamma}-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

doi:10.1371/journal.pone.0034552