Transcription profiling of human metastatic melanoma biopsies - non-supervised hierarchical clustering of gene expression data
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ABSTRACT: 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 performed 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 6 chemokines (CCL2, CCL3, CCL4, CCL5, CXCL9, and CXCL10) was confirmed by protein array and/or quantitative RT-PCR to be preferentially expressed in tumors that contained T cells. Corresponding chemokine receptors were found to be upregulated 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 produced a similar broad array of chemokines. These melanoma cells more effectively recruited human CD8+ effector T cells when implanted as xenografts in NOD/scid 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 anti-tumor immunity. Experiment Overall Design: To examine associations between CD8 expression and a diverse panel of chemokines, affymetrix gene expression profiling performed on a series of metastatic melanoma biopsies. Non-supervised hierarchical clustering analysis revealed a major segregation of samples based on the presence or absence of T-cell-associated transcripts.
ORGANISM(S): Homo sapiens
SUBMITTER: zha yuanyuan
PROVIDER: S-ECPF-GEOD-12627 | biostudies-other |
REPOSITORIES: biostudies-other
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