title: Interleukin-1 is required for cancer eradication mediated by tumor-specific Th1 cells.
abstract: The role of inflammation in cancer is controversial as both tumor-promoting and tumor-suppressive aspects of inflammation have been reported. In particular, it has been shown that pro-inflammatory cytokines, like interleukin-1α (IL-1α), IL-1β, IL-6, and tumor necrosis factor α (TNFα), may either promote or suppress cancer. However, the cellular and molecular basis underlying these opposing outcomes remains enigmatic. Using mouse models for myeloma and lymphoma, we have recently reported that inflammation driven by tumor-specific T helper 1 (Th1) cells conferred protection against B-cell cancer and that interferon-γ (IFN-γ) was essential for this process. Here, we have investigated the contribution of several inflammatory mediators. Myeloma eradication by Th1 cells was not affected by inhibition of TNF-α, TNF-related weak inducer of apoptosis (TWEAK), or TNF-related apoptosis-inducing ligand (TRAIL). In contrast, cancer elimination by tumor-specific Th1 cells was severely impaired by thein vivoneutralization of both IL-1α and IL-1β (collectively named IL-1) with IL-1 receptor antagonist (IL-1Ra). The antitumor functions of tumor-specific Th1 cells and tumor-infiltrating macrophages were both affected by IL-1 neutralization. Secretion of the Th1-derived cytokines IL-2 and IFN-γ at the incipient tumor site was severely reduced by IL-1 blockade. Moreover, IL-1 was shown to synergize with IFN-γ for induction of tumoricidal activity in tumor-infiltrating macrophages. This synergy between IL-1 and IFN-γ may explain how inflammation, when driven by tumor-specific Th1 cells, represses rather than promotes cancer. Collectively, the data reveal a central role of inflammation, and more specifically of the canonical pro-inflammatory cytokine IL-1, in enhancing Th1-mediated immunity against cancer.
authors.affiliation: Centre for Immune Regulation; University of Oslo and Oslo University Hospital Rikshospitalet ; Oslo, Norway.
authors.forename: Ole Audun Werner
authors.initials: OA
authors.lastname: Haabeth
authors.affiliation: Centre for Immune Regulation; University of Oslo and Oslo University Hospital Rikshospitalet ; Oslo, Norway.
authors.forename: Kristina Berg
authors.initials: KB
authors.lastname: Lorvik
authors.affiliation: Department of Immunology; Juntendo University School of Medicine ; Tokyo, Japan.
authors.forename: Hideo
authors.initials: H
authors.lastname: Yagita
authors.affiliation: Centre for Immune Regulation; University of Oslo and Oslo University Hospital Rikshospitalet; Oslo, Norway; K.G. Jebsen Centre for Influenza Vaccine Research; University of Oslo; Oslo, Norway.
authors.forename: Bjarne
authors.initials: B
authors.lastname: Bogen
authors.affiliation: Centre for Immune Regulation; University of Oslo and Oslo University Hospital Rikshospitalet ; Oslo, Norway.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Corthay
keywords: CD4+ T cells; IFN-γ; IL-1RA; IL-1α; IL-1β; IL-21; IL-27; Th1; and IL33; cancer immunosurveillance; inflammation; macrophages