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Alterations of costimulatory molecules and instructive cytokines expressed by dendritic cells in the microenvironment of an endogenous mouse lymphoma

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Abstract

Costimulatory surface molecules and instructive cytokines expressed by dendritic cells (DCs) determine the outcome of an immune response. In malignant disease, DCs are often functionally compromised. In most tumors studied so far, the deficient induction of effective T cell responses has been associated with a blockade of DC maturation, but little has been known on DCs infiltrating malignant B cell lymphoma. Here, we investigated for the first time the phenotypic and functional status of DCs in B cell lymphoma, and we analyzed the network of DCs, tumor cells, natural killer (NK) cells and cytokines present in the tumor micromilieu. Therefor, we used an endogenous myc-transgenic mouse lymphoma model, because transplanted tumor cells foster an IFN-γ-driven Th1 antitumor response rather than an immunosuppressive environment, which is observed in autochthonous neoplasias. Lymphoma-infiltrating DCs showed a mature phenotype and a Th2-inducing cytokine pattern. This situation is in contrast to most human malignancies and mouse models described. Cellular contacts between DCs and tumor cells, which involved CD62L on the lymphoma, caused upregulation of costimulatory molecules, whereas IL-10 primarily derived from lymphoma cells induced an IL-12/IL-10 shift in DCs. Thus, alteration of costimulatory molecules and instructive cytokines was mediated by distinct mechanisms. Normal NK cells were able to additionally modulate DC maturation but this effect was absent in the lymphoma environment where IFN-γ production by NK cells was severely impaired. These data are relevant for establishing novel immunotherapeutic approaches against B cell lymphoma.

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Acknowledgments

The work was supported by grants from Wilhelm-Sander-Stiftung (2010.108.1) and from Deutsche Krebshilfe (109036 and 109037). We thank A. Geishauser and M. Hagemann for expert technical assistance and S. Edelmann for providing OT-I and OT-II mice. This paper includes parts of the doctoral theses of Marcella Naujoks, Jakob Weiß, Tanja Riedel and Margarethe Przewoznik at the Ludwig-Maximilians-Universität München.

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The authors declare no financial or commercial conflict of interest.

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Authors and Affiliations

  1. Institut für Molekulare Immunologie, Helmholtz-Zentrum München, Marchioninistr. 25, 81377, Munich, Germany

    Marcella Naujoks, Jakob Weiß, Tanja Riedel, Nadine Hömberg, Margarethe Przewoznik, Elfriede Noessner & Ralph Mocikat

  2. Department of Dermatology, Eberhard-Karls-Universität, Tübingen, Germany

    Martin Röcken

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  1. Marcella Naujoks
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  2. Jakob Weiß
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  4. Nadine Hömberg
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  5. Margarethe Przewoznik
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  6. Elfriede Noessner
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  7. Martin Röcken
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  8. Ralph Mocikat
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Corresponding author

Correspondence to Ralph Mocikat.

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Marcella Naujoks and Jakob Weiß have contributed equally to this work.

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Naujoks, M., Weiß, J., Riedel, T. et al. Alterations of costimulatory molecules and instructive cytokines expressed by dendritic cells in the microenvironment of an endogenous mouse lymphoma. Cancer Immunol Immunother 63, 491–499 (2014). https://doi.org/10.1007/s00262-014-1538-7

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  • DOI: https://doi.org/10.1007/s00262-014-1538-7

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