The Journal of Experimental Medicine
StemCell Technologies
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Published online 27 October 2003 doi:10.1084/jem.20030593
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© Rockefeller University Press, 0022-1007/2003/11/1337 $5.00
The Journal of Experimental Medicine, Volume 198, Number 9, 1337-1347

Immune Evasion by Murine Melanoma Mediated through CC Chemokine Receptor-10

Takashi Murakami1, Adela R. Cardones1, Steven E. Finkelstein2, Nicholas P. Restifo2, Brenda A. Klaunberg5, Frank O. Nestle4, S. Sianna Castillo3, Phillip A. Dennis3 and Sam T. Hwang1

1 Dermatology, CCR, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD 20892
2 Surgery, CCR, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD 20892
3 Cancer Therapeutics Branches, CCR, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD 20892
4 National Institute of Neurological Disorders and Stroke, Bethesda, MD 20892
5 Department of Dermatology, University of Zürich Hospital, CH-8091 Zürich, Switzerland

Address correspondence to Sam T. Hwang, Bldg. 10/Rm. 12N246, 10 Center Dr., Bethesda, MD 20892-1908. Phone: (301) 496-8724; Fax: (301) 496-5370; email: hwangs{at}mail.nih.gov

Human melanoma cells frequently express CC chemokine receptor (CCR)10, a receptor whose ligand (CCL27) is constitutively produced by keratinocytes. Compared with B16 murine melanoma, cells rendered more immunogenic via overexpression of luciferase, B16 cells that overexpressed both luciferase and CCR10 resisted host immune responses and readily formed tumors. In vitro, exposure of tumor cells to CCL27 led to rapid activation of Akt, resistance to cell death induced by melanoma antigen-specific cytotoxic T cells, and phosphatidylinositol-3-kinase (PI3K)–dependent protection from apoptosis induced by Fas cross-linking. In vivo, cutaneous injection of neutralizing antibodies to endogenous CCL27 blocked growth of CCR10-expressing melanoma cells. We propose that CCR10 engagement by locally produced CCL27 allows melanoma cells to escape host immune antitumor killing mechanisms (possibly through activation of PI3K/Akt), thereby providing a means for tumor progression.

Key Words: metastasis • chemokine receptor • cancer • cell signaling


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