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Immune reconstitution prevents metastatic recurrence of murine osteosarcoma

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Abstract

Primary tumors developing in immunocompetent hosts escape immunosurveillance by acquiring immune evasive properties. This raises the prospect that metastases derived from such tumors will also evade immunity. To investigate whether immune surveillance plays a role in preventing metastases, we studied a murine model which mimics the clinical progression of osteosarcoma: primary tumor growth in the lower extremity, amputation, minimal residual disease followed by the development of overt metastases. K7M2 implants readily escaped immune surveillance since normal BALB/c mice, T cell deficient SCID and T/NK cell deficient SCID-bg mice showed no difference in the rate of growth of primary osteosarcomas. However, both SCID and SCID-bg mice had higher rates of metastases than immunocompetent mice. Similarly, immune reconstitution following transfer of naive T cells to SCID or SCID-bg mice did not impact primary tumor growth, but significantly diminished metastatic recurrence. T cells in osteosarcoma bearing mice produced IFNγ in response to tumor and IFNγ production by immune reconstituting T cells was required to prevent metastases. These results demonstrate an important role for T cell based immune surveillance in preventing metastases, even when metastases develop from tumors that adeptly evade immunosurveillance. The results further suggest that T cell depleting cancer therapies may eliminate beneficial immune responses and that immune reconstitution of lymphopenic cancer patients could prevent metastatic recurrence of solid tumors.

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Acknowledgments

The authors would like to thank Dr. Jon Wigginton for kindly providing the IFNγ deficient mice. This work was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research.

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Authors and Affiliations

  1. Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA

    Melinda S. Merchant, Fraia Melchionda, Manoj Sinha, Chand Khanna, Lee Helman & Crystal L. Mackall

  2. Department of Pediatric Hematology-Oncology, S. Orsola Hospital, University of Bologna, Bologna, Italy

    Fraia Melchionda

  3. 10-CRC/1W-3940, 10 Center Dr., MSC 1104, Bethesda, MD, 20892, USA

    Crystal L. Mackall

Authors
  1. Melinda S. Merchant
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  2. Fraia Melchionda
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  5. Lee Helman
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  6. Crystal L. Mackall
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Correspondence to Crystal L. Mackall.

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By acceptance of this article, the publisher or recipient acknowledges right of the U.S. Government to retain a nonexclusive, royalty-free license in and to any copyright covering the article.

The contents of this publication do not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. Animal care was provided in accordance with procedures outlined in the “Guide for the Care and Use of Laboratory Animals” (NIH Pub. No. 86-23, 1996). This project was funded in whole or part with funds from the National Cancer Institute, National Institutes of Health, under Contract No. NO1-CO-56000.

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Merchant, M.S., Melchionda, F., Sinha, M. et al. Immune reconstitution prevents metastatic recurrence of murine osteosarcoma. Cancer Immunol Immunother 56, 1037–1046 (2007). https://doi.org/10.1007/s00262-006-0257-0

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  • DOI: https://doi.org/10.1007/s00262-006-0257-0

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