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Host-Derived Interleukin-1 Is Important in Determining the Immunogenicity of 3-Methylcholantrene Tumor Cells¹

Moshe Elkabets^*, Yakov Krelin^*, Shahar Dotan^*, Adelheid Cerwenka, Angel Porgador^*, Rachel G. Lichtenstein^*,, Malka R. White^*, Margot Zoller, Yoichizo Iwakura^¶, Charles A. Dinarello, Elena Voronov^* and Ron N. Apte^2,*

^* The Shraga Segal Department of Microbiology and Immunology and Faculty of Health Sciences and The Cancer Research Center, Ben-Gurion University of the Negev, Beer-Sheva, Israel; German Cancer Research Center (DKFZ), Division of Innate Immunity (A.C.), and Department of Tumor Progression and Tumor Defense (M.Z.), Heidelberg, Germany; and Department of Medicine, University of Colorado Health Sciences Center, Denver, CO 80262; Department of Biotechnology, Faculty of Engineering Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel; and ^¶ Institute of Medical Science, University of Tokyo, Tokyo, Japan

Using IL-1/IL-1Ra knockout BALB/c mice, we showed that 3-methylcholatrene (3-MCA)-induced carcinogenesis is dependent on IL-1β-induced inflammatory responses. Patterns of local inflammation and tumorigenicity were similar in wild-type (WT) and IL-1^–/– mice, while in IL-1β^–/– mice, tumorigenicity was attenuated and in IL-1Ra^–/– mice accentuated. 3-MCA-induced fibrosarcoma cell lines from WT mice developed into progressive tumors in WT mice, while surprisingly, lines from IL-1^–/– mice formed tumors only in immunocompromized mice. 3-MCA-induced fibrosarcoma cell lines from IL-1^–/– mice, compared with lines from WT mice, manifested higher expression levels of "global" surface molecules related to Ag presentation and interactions with immune surveillance cells (MHC class I, B7.1, B7.2, L-selectin, and NKG2D ligands) and were eradicated mainly by CD4⁺- and CD8⁺-dependent T cell responses. Concomitantly, at the injection site of 3-MCA-induced fibrosarcoma cells derived from IL-1^–/– mice, a leukocyte infiltrate, subsequently replaced by a scar-like tissue, was observed. Immune aberrations in NK cell maturation, antitumor specific immunity and killing capacity of effector cells were observed in IL-1^–/– mice, in contrast to WT mice. Thus, we demonstrate in this study the significance of host-derived IL-1 in cancer immunoediting, by affecting innate and specific immunosurveillance mechanisms. Overall, the results presented in this study, together with our previous studies, attest to differential involvement of IL-1 and IL-1β in tumorigenesis; host-derived IL-1β mainly controls inflammation, while concomitantly, IL-1 controls immunosurveillance of the arising malignant cells. Elucidation of the involvement of the IL-1 molecules in the malignant process will hopefully lead to the development of novel approaches for chemoprevention and immunotherapy.

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 R.N.A. was supported by the U.S.-Israel Binational Foundation (BSF), the Israel Ministry of Health Chief Scientist’s Office, and the German-Israeli DIP collaborative program (Deutsche-Israelische Projectkooperation). The Israel Science Foundation founded by the Israel Academy of Sciences and Humanities. National Institutes of Health Grants AI-15614, HL-68743, and CA-04 6934 (C.A. Dinarello). Cooperation Program in Cancer Research of the Deutsches Krebsforschungszentrum (DKFZ) and Israel’s Ministry of Science (MOS) (to A.P. and A.C.). R.N.A. is an incumbent of the Irving Isaac Sklar Chair in Endocrinology and Cancer. M.E. is supported by the ISEF Foundation and Nehemia-Lev-Zion scholarship.

² Address correspondence and reprint requests to Dr. Ron N. Apte, Department of Microbiology and Immunology, Faculty of Health Sciences and The Cancer Research Center, Ben-Gurion University of the Negev, Beer-Sheva, Israel. E-mail address: rapte{at}bgu.ac.il

³ Abbreviations used in this paper: 3-MCA, 3-methylcholatrene; WT, wild type; KO, knockout; PCNA, anti-proliferating cell nuclear Ag.

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