IL-18 Inhibits Growth of Murine Orthotopic Prostate Carcinomas via Both Adaptive and Innate Immune Mechanisms

Pamela Joan Russell,Irmgard Förster,Matthias Lochner,Carl Andrew Power,Vladimir Brusic,Brian Wan-Chi Tse

doi:10.1371/journal.pone.0024241

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.

Highlights

Prostate cancer (PCa) is the second most common cancer of men in the world [1]
This study demonstrates that IL-18 in the RM1 tumor environment, achieved either by IL-18 gene-introduction or direct injection can slow the growth of both subcutaneous and orthotopic tumors in in vivo models, provides proof of concept that IL-18 has potential as an immunotherapeutic agent for prostate cancer
The difference in growth patterns at the two anatomical sites highlights the importance of using orthotopic models to assess the effect of immunotherapy on tumour growth and the mechanisms involved in mediating such effects

Summary

Introduction

Prostate cancer (PCa) is the second most common cancer of men in the world [1]. In 2002, an estimated 679,000 men were newly diagnosed with PCa and an estimated 221,000 died from it [1]. PCa is often considered as an ideal candidate for cancer immunotherapy because of the expression of prostate specific molecules and the non-essential nature of the prostate gland [3]. Experiments using mice have shown that the immune stimulatory effects of some cytokines can induce strong anti-tumor immunity [4]. This involves both innate and adaptive immune mechanisms that function complimentarily to promote tumor immunity [5]

Methods

Results

Conclusion