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Chemokine Expression in Melanoma Metastases Associated with CD8⁺ T-Cell Recruitment

¹ Department of Pathology, ² Department of Medicine, Section of Hematology/Oncology, and ³ Department of Surgery, The University of Chicago, Chicago, Illinois and ⁴ The University of Virginia, Charlottesville, Virginia

Requests for reprints: Thomas F. Gajewski, University of Chicago, 5841 South Maryland Avenue, MC2115, Chicago, IL 60637. Phone: 773-702-4601; Fax: 773-702-3163; E-mail: tgajewsk{at}medicine.bsd.uchicago.edu.

Key Words: Chemokines • Melanoma • T cells

Despite the frequent detection of circulating tumor antigen–specific T cells, either spontaneously or following active immunization or adoptive transfer, immune-mediated cancer regression occurs only in the minority of patients. One theoretical rate-limiting step is whether effector T cells successfully migrate into metastatic tumor sites. Affymetrix gene expression profiling done on a series of metastatic melanoma biopsies revealed a major segregation of samples based on the presence or absence of T-cell–associated transcripts. The presence of lymphocytes correlated with the expression of defined chemokine genes. A subset of six chemokines (CCL2, CCL3, CCL4, CCL5, CXCL9, and CXCL10) was confirmed by protein array and/or quantitative reverse transcription-PCR to be preferentially expressed in tumors that contained T cells. Corresponding chemokine receptors were found to be up-regulated on human CD8⁺ effector T cells, and transwell migration assays confirmed the ability of each of these chemokines to promote migration of CD8⁺ effector cells in vitro. Screening by chemokine protein array identified a subset of melanoma cell lines that produced a similar broad array of chemokines. These melanoma cells more effectively recruited human CD8⁺ effector T cells when implanted as xenografts in nonobese diabetic/severe combined immunodeficient mice in vivo. Chemokine blockade with specific antibodies inhibited migration of CD8⁺ T cells. Our results suggest that lack of critical chemokines in a subset of melanoma metastases may limit the migration of activated T cells, which in turn could limit the effectiveness of antitumor immunity. [Cancer Res 2009;69(7):3077–85]