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* Cancer and Inflammation Program, Science Applications International Corporation-Frederick, National Cancer Institute-Frederick,
Laboratory of Experimental Immunology,
Laboratory of Molecular Immunoregulation,
Human Retrovirus Section,
¶ Human Retrovirus Pathogenesis Section, Vaccine Branch, and
|| Data Management Services, NCI-Frederick, Frederick, MD 21702;
# Pediatric Oncology Branch, National Cancer Institute, Bethesda, MD 20892 and
** Department of Discovery Biology, Schering-Plough Biopharma, Palo Alto, CA 94304
IL-27 exerts antitumor activity in murine orthotopic neuroblastoma, but only partial antitumor effect in disseminated disease. This study demonstrates that combined treatment with IL-2 and IL-27 induces potent antitumor activity in disseminated neuroblastoma metastasis. Complete durable tumor regression was achieved in 90% of mice bearing metastatic TBJ-IL-27 tumors treated with IL-2 compared with only 40% of mice bearing TBJ-IL-27 tumors alone and 0% of mice bearing TBJ-FLAG tumors with or without IL-2 treatment. Comparable antitumor effects were achieved by IL-27 protein produced upon hydrodynamic IL-27 plasmid DNA delivery when combined with IL-2. Although delivery of IL-27 alone, or in combination with IL-2, mediated pronounced regression of neuroblastoma metastases in the liver, combined delivery of IL-27 and IL-2 was far more effective than IL-27 alone against bone marrow metastases. Combined exposure to IL-27 produced by tumor and IL-2 synergistically enhances the generation of tumor-specific CTL reactivity. Potentiation of CTL reactivity by IL-27 occurs via mechanisms that appear to be engaged during both the initial sensitization and effector phase. Potent immunologic memory responses are generated in mice cured of their disseminated disease by combined delivery of IL-27 and IL-2, and depletion of CD8+ ablates the antitumor efficacy of this combination. Moreover, IL-27 delivery can inhibit the expansion of CD4+CD25+Foxp3+ regulatory and IL-17-expressing CD4+ cells that are otherwise observed among tumor-infiltrating lymphocytes from mice treated with IL-2. These studies demonstrate that IL-27 and IL-2 synergistically induce complete tumor regression and long-term survival in mice bearing widely metastatic neuroblastoma tumors.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract N01-CO-12400. The content of this publication does 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. This research was supported in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. We also gratefully acknowledge the generous support of these studies by the Children’s Cancer Foundation. By acceptance of this article, the publisher or recipient acknowledges the right of the U.S. Government to retain a nonexclusive, royalty-free license in and to any copyright covering the article.
2 Address correspondence and reprint requests to Dr. Rosalba Salcedo, Cancer and Inflammation Program, National Cancer Institute Center for Cancer Research, Basic Research Program, Science Applications International Corporation-Frederick, National Cancer Institute-Frederick Building 567, Room 207, Frederick, MD 21702-1201. E-mail address: lmirosi{at}ncifcrf.gov
3 Abbreviations used in this paper: TIL, tumor infiltrating lymphocyte; FET, Fisher’s exact test.
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