title: IL-18 inhibits growth of murine orthotopic prostate carcinomas via both adaptive and innate immune mechanisms.
abstract: 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.
authors.affiliation: Lowy Cancer Research Centre, University of New South Wales, Sydney, New South Wales, Australia.
authors.forename: Brian Wan-Chi
authors.initials: BW
authors.lastname: Tse
authors.forename: Pamela Joan
authors.initials: PJ
authors.lastname: Russell
authors.forename: Matthias
authors.initials: M
authors.lastname: Lochner
authors.forename: Irmgard
authors.initials: I
authors.lastname: Förster
authors.forename: Carl Andrew
authors.initials: CA
authors.lastname: Power
mesh_terms: D056704:Adaptive Immunity / Q000276:immunology*; D000818:Animals; D002277:Carcinoma / Q000378:metabolism*; D045744:Cell Line, Tumor; D018932:Chemokine CCL2 / Q000378:metabolism; D018946:Chemokine CCL5 / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D007113:Immunity, Innate / Q000276:immunology*; D007150:Immunohistochemistry; D007371:Interferon-gamma / Q000378:metabolism; D018664:Interleukin-12 / Q000378:metabolism; D020382:Interleukin-18 / Q000378:metabolism*; D015847:Interleukin-4 / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011471:Prostatic Neoplasms / Q000378:metabolism*
chemical_list: C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D018946:Chemokine CCL5; D020382:Interleukin-18; D018664:Interleukin-12; D015847:Interleukin-4; D007371:Interferon-gamma; D016178:Granulocyte-Macrophage Colony-Stimulating Factor