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* Cancer Immunology Program, Trescowthick Laboratories, Peter MacCallum Cancer Centre, St. Andrews Place, East Melbourne, Victoria, Australia;
Department of Pathology and Immunology, Center for Immunology, Washington University School of Medicine, St. Louis, MO 63110; and
Centre for Functional Genomics and Human Disease, Monash Institute of Medical Research, Monash University, Clayton, Victoria, Australia
This study demonstrates that type I IFNs are an early and critical regulator of NK cell numbers, activation, and antitumor activity. Using both IFNAR1- and IFNAR2-deficient mice, as well as an IFNAR1-blocking Ab, we demonstrate that endogenous type I IFN is critical for controlling NK cell-mediated antitumor responses in many experimental tumor models, including protection from methylcholanthrene-induced sarcomas, resistance to the NK cell-sensitive RMA-S tumor and cytokine immunotherapy of lung metastases. Protection from RMA-S afforded by endogenous type I IFN is more potent than that of other effector molecules such as IFN-
, IL-12, IL-18, and perforin. Furthermore, cytokine immunotherapy using IL-12, IL-18, or IL-21 was effective in the absence of endogenous type I IFN, however the antimetastatic activity of IL-2 was abrogated in IFNAR-deficient mice, primarily due to a defect in IL-2-induced cytotoxic activity. This study demonstrates that endogenous type I IFN is a central mediator of NK cell antitumor responses.
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 J.B.S. was supported by an Australian Postgraduate Award. M.J.S. and P.J.H. are supported by a National Health and Medical Research Council of Australia (NH&MRC) Senior Principal Research Fellowship. The project was supported by a Program Grant from the NH&MRC and GlaxoSmithKline. R.D.S. and K.C.F.S. were supported by grants from the National Cancer Institute, the Ludwig Institute for Cancer Research, and the Cancer Research Institute.
2 Address correspondence and reprint requests to Dr. Mark Smyth, Cancer Immunology Program, Peter MacCallum Cancer Centre, Locked Bag 1, A’Beckett St., 8006, Victoria, Australia. E-mail address: mark.smyth{at}petermac.org
3 Abbreviations used in this paper: MCA, methylcholanthrene; WT, wild type; 3LL, Lewis lung carcinoma; asGM1, asialo GM1; pDC, plasmacytoid dentritic cell.
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