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*Department of Pathology,
Department of Microbiology & Immunology, and
Department of Pediatrics, Dalhousie University, Halifax, Nova Scotia, Canada;
Molecular Preventive Medicine, Graduate School of Medicine, Tokyo University, Tokyo, Japan
Invariant NKT (iNKT) cells can induce potent antitumor responses in vivo. However, the mechanisms that regulate the effects of iNKT cells are unclear. The chemokine receptor CXCR6, and its ligand CXCL16, have been shown to play critical roles in iNKT cell homeostasis and activation. Thus we investigated the role of CXCR6 in protection against experimental metastasis of B16-F10 melanoma (B16) and Lewis lung carcinoma (LLC) cells to the liver and lungs. Wild-type and CXCR6–/– mice exhibited no differences in tumor cell metastasis to the lungs. However, metastasis of LLC and B16 tumor cells to the liver was enhanced in CXCR6–/– mice. Liver metastasis was also increased in wild-type mice treated with a CXCL16 neutralizing Ab. As Ab treatments did not alter iNKT cell numbers, this implicates a direct role for CXCR6/CXCL16 in regulating antitumor immunity. Cytokine induction was significantly attenuated in CXCR6–/– mice upon systemic iNKT cell activation with the glycolipid Ags 
-galactosylceramide (-GalCer), -C-GalCer (a Th1 polarizing derivative), or OCH (a Th2 polarizing derivative). Despite differences in the levels of cytokine production, liver and lung metastasis were inhibited significantly in both wild-type and CXCR6–/– mice treated with glycolipids. Single doses of -GalCer, -C-GalCer, or OCH were sufficient to prevent liver metastasis and subsequent doses failed to elicit optimal cytokine responses. Our findings implicate a role for CXCR6 in natural immunosurveillance against liver metastasis. However, CXCR6 deficiency could be overcome by systemic iNKT cell activation, demonstrating that even suboptimal iNKT cell activation can protect against metastasis.
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 a grant from the Canadian Cancer Society (to B.J.) by the National Cancer Institute of Canada. B.J. holds the Canada Research Chair in Inflammation and Immunity. R.C. is the recipient of a Cancer Research Training Program Award with funding from the Dalhousie Cancer Research Program. E.G. is the recipient of a studentship from the Nova Scotia Health Research Foundation.
2 R.C. and E.G. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Brent Johnston, Department of Microbiology & Immunology, Dalhousie University, 5850 College Street, Halifax, Nova Scotia B3H 1X5, Canada. E-mail address: Brent.Johnston{at}Dal.ca
4 Abbreviations used in this paper: iNKT, invariant NKT cell; -GalCer, -galactosylceramide; DC, dendritic cell; LLC, Lewis lung carcinoma.
5 The online version of this article contains supplemental material.
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