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CXC Chemokine Ligand 9/Monokine Induced by IFN- Production by Tumor Cells Is Critical for T Cell-Mediated Suppression of Cutaneous Tumors¹

Anton V. Gorbachev^2,3,*, Hirohito Kobayashi^3,*, Daisuke Kudo^*, Charles S. Tannenbaum^*, James H. Finke^*, Suyu Shu, Joshua M. Farber and Robert L. Fairchild^*

^* Department of Immunology and Center for Surgery Research, Cleveland Clinic, Cleveland, OH 44195, and Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892

The role of tumor-produced chemokines in the growth of malignancies remains poorly understood. We retrieved an in vivo growing MCA205 fibrosarcoma and isolated tumor cell clones that produce both CXCL9/monokine induced by IFN- (Mig) and CXCL10/IFN--inducible protein 10 following stimulation with IFN- and clones that produce IFN--inducible protein 10 but not Mig. The Mig-deficient variants grew more aggressively as cutaneous tumors in wild-type mice than the Mig-producing tumor cells. The growth of Mig-expressing, but not Mig-deficient, tumor cells was suppressed by NK and T cell activity. Transduction of Mig-negative variants to generate constitutive tumor cell production of Mig resulted in T cell-dependent rejection of the tumors and in induction of protective tumor-specific CD8⁺ T cell responses to Mig-deficient tumors. The results indicate a critical role for tumor-derived Mig in T cell-mediated responses to cutaneous fibrosarcomas and suggest the loss of Mig expression as a mechanism used by tumor cells to evade these 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 This work was supported by National Institutes of Health Grant RO1AI45888.

² Address correspondence and reprint requests to Dr. Anton V. Gorbachev, Lerner Research Institute, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195-0001. E-mail address: gorbaca{at}ccf.org

³ A.V.G. and H.K. contributed equally to this work and share principal coauthorship.

⁴ Abbreviations used in this paper: Mig, monokine induced by IFN-; IP-10, IFN--inducible protein 10; MCA, methylcholanthrene; RPA, RNase protection assay; RT, room temperature.

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