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Chemokine expression in melanoma metastases associated with CD8+ T-cell recruitment.

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 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.

SUBMITTER: Harlin H

PROVIDER: S-EPMC3886718 | biostudies-literature | 2009 Apr

REPOSITORIES: biostudies-literature

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Chemokine expression in melanoma metastases associated with CD8+ T-cell recruitment.

Harlin Helena H Meng Yuru Y Peterson Amy C AC Zha Yuanyuan Y Tretiakova Maria M Slingluff Craig C McKee Mark M Gajewski Thomas F TF

Cancer research 20090317 7

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 ...[more]

PMID: 19293190

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Project description:In chronic viral infections such as HIV-1, HBV and HCV, CD8+ T cells may become ”exhausted”, characterized by progressive functional deficiency. Recently, the underlying mechanisms have been characterized by molecular profiling of virus-specific CD8+ T cells. In contrast, only little is known of self/tumor-specific CD8+ T cells from cancer patients, likely because they are much more difficult to assess. For the first time, we determined the molecular profile of human tumor-specific CD8+ T cells, upon sorting of Melan-A/MART-1 specific T cells directly ex vivo from 19 melanoma patients after vaccination with peptide and CpG. For comparison, we sorted protective T cells specific for the two herpes viruses EBV and CMV. In peripheral blood, we found multiple features of functional effector T cells, with only small but nevertheless significant differences between the three T cell populations, resulting in clean clustering according to antigen specificity. In contrast, Melan-A/MART-1 specific T cells obtained from tumor-infiltrated lymph nodes (TILNs) expressed multiple genes associated with T cell exhaustion, compatible with the known functional deficiencies of T cells in melanoma metastases. We show that individual T cells simultaneously expressed multiple inhibitory receptors implied in functional impairment. Together, the data indicate that in circulation, human tumor-specific T cells have the potential to become competent effector cells. In the tumor environment, however, T cells are exhausted and fail to control malignant disease. Our novel resource data identify mechanisms of functional T cell deficiency in melanoma patients, providing a rational basis for the improvement of immune therapy. 52 samples were measured in two sets of experiments. 4 self/tumor-specific samples from blood were replicated between the first and second sets. Set 1 (32 samples, all from blood): 13 naive samples, 10 EBV-specific samples, 9 self/tumor-specific samples. Set 2 (20 samples): 7 CMV-specific samples from blood, 7 self/tumor-specific samples from TILN, 6 self/tumor-specific samples from blood.

Dataset Information

Chemokine expression in melanoma metastases associated with CD8+ T-cell recruitment.

Publications

Chemokine expression in melanoma metastases associated with CD8+ T-cell recruitment.

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