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In vivo responses to vaccination with Mage-b, GM-CSF and thioglycollate in a highly metastatic mouse breast tumor model, 4T1

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Abstract

Metastatic breast cancer is an important contributor to morbidity and mortality. Hence, new therapies are needed that target breast cancer metastases. Here, we focus on Mage-b as a possible vaccine target to prevent the development of breast cancer metastases, through activation of Mage-b-specific cytotoxic T lymphocytes (CTL). The syngeneic cell line 4T1, highly expressing Mage-b, was used as a pre-clinical metastatic mouse breast tumor model. BALB/c mice received three preventive intraperitoneal immunizations with Mage-b DNA vaccine mixed with plasmid DNA, secreting granulocyte–macrophage colony stimulating factor (GM-CSF). In addition, antigen-presenting cells were more efficiently recruited to the peritoneal cavity by the injection of thioglycollate broth (TGB), prior to each immunization. Immunization with Mage-b/GM-CSF/TGB significantly reduced the number of metastases by 67% compared to the saline/GM-CSF/TGB and by 69% compared to the vector control/GM-CSF/TGB. Also, tumor growth was significantly reduced by 45% in mice vaccinated with Mage-b/GM-CSF/TGB compared to the saline/GM-CSF/TGB and by 47% compared to the control vector/GM-CSF/TGB group. In vivo, the number of CD8 T cells significantly increased in the primary tumors and metastases of mice vaccinated with Mage-b/GM-CSF/TGB compared to the saline/GM-CSF/TGB and the control vector/GM-CSF/TGB group, while the number of CD4 T cells significantly decreased. The combination of Mage-b, GM-CSF and TGB did not only induce significantly higher levels of IFNγ in the lymph nodes of vaccinated compared to control mice, but also induced significantly higher expression levels of Fas-ligand (FasL) in the primary tumors (expressing Fas protein constitutively), compared to the control mice. Whether the interaction between Fas and FasL may have contributed to the smaller tumors needs to be further analyzed.

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Acknowledgments

Authors gratefully acknowledge Rita Busuttil, Ana-Maria Garcia, Shanique Leonard, and Karl Rodriguez, for their excellent technical assistance in the mouse studies. This work was supported by The American Federation for Aging Research (AFAR) A000106 grant, and by NIA grant 1RO1 AG023096-01.

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Authors and Affiliations

  1. California Pacific Medical Center Research Institute, 475 Brannan Street, San Francisco, CA, 94107, USA

    Claudia Gravekamp, Francisco Castro, Sun Hee Kim & Dan Moore

  2. Department of Cellular and Structural Biology, University of Texas Health Science Center San Antonio, 15355 Lambda Drive, San Antonio, TX, 78245, USA

    Belinda Leal & Ashley Denny

  3. Buck Institute for Age Research, 8001 Redwood Blvd, Novato, CA, 94945, USA

    Rumana Bahar

  4. Department of Pathology, University of Texas Health Science Center San Antonio, 7703 Floyd Curl Drive, San Antonio, TX, 78229, USA

    Shellye Lampkin & Robert Reddick

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  1. Claudia Gravekamp
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Correspondence to Claudia Gravekamp.

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Gravekamp, C., Leal, B., Denny, A. et al. In vivo responses to vaccination with Mage-b, GM-CSF and thioglycollate in a highly metastatic mouse breast tumor model, 4T1. Cancer Immunol Immunother 57, 1067–1077 (2008). https://doi.org/10.1007/s00262-007-0438-5

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  • DOI: https://doi.org/10.1007/s00262-007-0438-5

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