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CD200-CD200R signaling suppresses anti-tumor responses independently of CD200 expression on the tumor

Oncogene volume 31, pages 2979–2988 (2012)Cite this article

Abstract

Expression of CD200, the gene encoding the ligand for the inhibitory immune receptor CD200R, is an independent prognostic factor for various forms of leukemia predicting worse overall survival of the patients. The enhanced expression of CD200 on the tumors implies that anti-tumor responses can be enhanced by blockage of the CD200–CD200R interaction. Indeed, antibody-mediated blockade of the CD200-CD200R inhibitory axis is currently evaluated in clinical tests to boost immune responses against CD200-expressing tumors. Here, we show that mice lacking CD200, the exclusive ligand for CD200R, are resistant to chemical skin carcinogenesis. Importantly, CD200R controls tumor outgrowth independently of CD200 expression by the tumor cells themselves. Furthermore, Cd200−/− mice do not become tolerant to intranasally administered antigens, suggesting that tumor rejection is normally suppressed through CD200-induced immune tolerance. Decreased tumor outgrowth is accompanied by increased expression of the proinflammatory cytokines interleukin (IL)-1β and IL-6 by the lymph node (LN) dendritic cells. During carcinogenesis, skin-draining LNs of Cd200−/− mice contain increased numbers of IL-17-producing FoxP3+ cells, which preferentially home to the tumors. Thus, the CD200-CD200R axis induces tolerance to external and tumor antigens and influences the T-regulatory/Th17 cell ratio. We demonstrate for the first time that the absence of CD200R signaling inhibits outgrowth of an endogenous tumor irrespective of CD200 expression by the tumor cells. This important paradigm shift leads to a much broader applicability of CD200-blockade in the treatment of tumors.

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Acknowledgements

We thank Gerrit Spierenburg for cell sorting, Serge van de Pavert for assistance with the confocal microscope and Lewis Lanier, Frank Miedema, Berent Prakken and Erik Hack for critical review of versions of this manuscript. This research was supported by the Association for International Cancer Research (AICR 07-0086) to LM and TPR and by a VICI grant (918.56.612) (from the Netherlands Organization for Scientific Research) to REM, MJG and RM.

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Authors and Affiliations

  1. Department of Immunology, University Medical Center Utrecht, Utrecht, The Netherlands

    T P Rygiel, G Karnam, R A van Schaarenburg & L Meyaard

  2. Department of Molecular Cell Biology and Immunology, VU Medical Center, Amsterdam, The Netherlands

    G Goverse, A P J van der Marel, M J Greuter, R Molenaar & R E Mebius

  3. Department of Metabolic and Endocrine Diseases and Netherlands Metabolomics Center, Utrecht, The Netherlands

    W F Visser & A B Brenkman

  4. Department of Experimental Immunology, Academic Medical Center, Amsterdam, The Netherlands

    R M Hoek

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  1. T P Rygiel
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Correspondence to L Meyaard.

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Rygiel, T., Karnam, G., Goverse, G. et al. CD200-CD200R signaling suppresses anti-tumor responses independently of CD200 expression on the tumor. Oncogene 31, 2979–2988 (2012). https://doi.org/10.1038/onc.2011.477

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