IL-18 inhibits growth of murine orthotopic prostate carcinomas via both adaptive and innate immune mechanisms
Data(s) |
2011
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Resumo |
Interleukin(IL)-18 is a pleiotrophic cytokine with functions in immune modulation, angiogenesis and bone metabolism. In this study, the potential of IL-18 as an immunotherapy for prostate cancer (PCa) was examined using the murine model of prostate carcinoma, RM1 and a bone metastatic variant RM1(BM)/B4H7-luc. RM1 and RM1(BM)/B4H7-luc cells were stably transfected to express bioactive IL-18. These cells were implanted into syngeneic immunocompetent mice, with or without an IL-18-neutralising antibody (αIL-18, SK113AE4). IL-18 significantly inhibited the growth of both subcutaneous and orthotopic RM1 tumors and the IL-18 neutralizing antibody abrogated the tumor growth-inhibition. In vivo neutralization of interferon-gamma (IFN-γ) completely eliminated the anti-tumor effects of IL-18 confirming an essential role of IFN-γ as a down-stream mediator of the anti-tumor activity of IL-18. Tumors from mice in which IL-18 and/or IFN-γ was neutralized contained significantly fewer CD4+ and CD8+ T cells than those with functional IL-18. The essential role of adaptive immunity was demonstrated as tumors grew more rapidly in RAG1−/− mice or in mice depleted of CD4+ and/or CD8+ cells than in normal mice. The tumors in RAG1−/− mice were also significantly smaller when IL-18 was present, indicating that innate immune mechanisms are involved. IL-18 also induced an increase in tumor infiltration of macrophages and neutrophils but not NK cells. In other experiments, direct injection of recombinant IL-18 into established tumors also inhibited tumor growth, which was associated with an increase in intratumoral macrophages, but not T cells. These results suggest that local IL-18 in the tumor environment can significantly potentiate anti-tumor immunity in the prostate and clearly demonstrate that this effect is mediated by innate and adaptive immune mechanisms. |
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application/pdf |
Identificador | |
Publicador |
Public Library of Science |
Relação |
http://eprints.qut.edu.au/52296/1/52296.pdf DOI:10.1371/journal.pone.0024241 Tse, Brian Wan-Chi, Russell, Pamela, Lochner, Matthias, Forster, Irmgard, & Power, Carl (2011) IL-18 inhibits growth of murine orthotopic prostate carcinomas via both adaptive and innate immune mechanisms. PLoS ONE, 6(9), e24241-1---12. http://purl.org/au-research/grants/NHMRC/497270 |
Direitos |
Copyright 2011 the authors This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
Fonte |
Faculty of Health; Institute of Health and Biomedical Innovation |
Tipo |
Journal Article |