Detection and Long-Term In Vivo Monitoring of Individual Tumor-Specific T Cell Clones in Patients with Metastatic Melanoma

• Published in: Journal of Immunology 2007-06, Vol.178 (11), p.6789-6795
• Main Authors: Michalek, Jaroslav, Kocak, Ivo, Fait, Vuk, Zaloudik, Jan, Hajek, Roman
• Format: Article
• Language: English
• Subjects: Adult; Aged; CD4-Positive T-Lymphocytes - chemistry; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - pathology; CD8-Positive T-Lymphocytes - chemistry; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - pathology; Clone Cells - chemistry; Clone Cells - immunology; Clone Cells - pathology; Epitopes, T-Lymphocyte - analysis; Epitopes, T-Lymphocyte - immunology; Female; Humans; Immunodominant Epitopes - analysis; Immunodominant Epitopes - immunology; Male; Melanoma - drug therapy; Melanoma - immunology; Melanoma - pathology; Melanoma - secondary; Middle Aged; Monitoring, Immunologic; Neoplastic Cells, Circulating - chemistry; Neoplastic Cells, Circulating - immunology; Neoplastic Cells, Circulating - pathology; T-Lymphocyte Subsets - chemistry; T-Lymphocyte Subsets - immunology; T-Lymphocyte Subsets - pathology; Tumor Cells, Cultured
• ISSN: 0022-1767; 1550-6606; 1365-2567
• DOI: 10.4049/jimmunol.178.11.6789

We investigated the presence of individual melanoma-specific T cell clones in patients with metastatic melanoma. Ten patients were examined for the presence of melanoma-reactive T cells using dendritic cells loaded with autologous tumor cells. Their specificity was tested using nonradioactive cytotoxicity test. Individual immunodominant T cell clones were identified by the clonotypic assay that combines in vitro cell culture, immunomagnetic sorting of activated IFN-gamma(+) T cells, TCRbeta locus-anchored RT-PCR, and clonotypic quantitative PCR. All patients had detectable melanoma-reactive T cells in vitro. Expanded melanoma-reactive T cells demonstrated specific cytotoxic effect against autologous tumor cells in vitro. Three patients experienced objective responses, and their clinical responses were closely associated with the in vivo expansion and long-term persistence of individual CD8(+) T cell clones with frequencies of 10(-6) to 10(-3) of all circulating CD8(+) T cells. Five patients with progressive disease experienced no or temporary presence of circulating melanoma-reactive T cell clones. Thus, circulating immunodominant CD8(+) T cell clones closely correlate with clinical outcome in patients with metastatic melanoma.