Abstract
To investigate the molecular mechanisms underlying altered T cell response in renal cell carcinoma (RCC) patients, we compared autologous and allogeneic CD8(+) T cell responses against RCC line from RCC patients and their HLA-matched donors, using mixed lymphocyte/tumor cell cultures (MLTCs). In addition, we analyzed the expression of molecules associated with cell cycle regulation. Autologous MLTC responder CD8(+) T cells showed cytotoxic activity against RCC cell lines; however the analysis of the distribution of CD8(+) T-cell subsets revealed that allogenic counterparts mediate superior antitumor efficacy. In RCC patients, a decreased proliferative response to tumor, associated with defects in JAK3/STAT5/6 expression that led to increased p27KIP1 expression and alterations in the cell cycle, was observed. These data define a molecular pathway involved in cell cycle regulation that is associated with the dysfunction of tumor-specific CD8(+) effector cells. If validated, this may define a therapeutic target in the setting of patients with RCC.
MeSH terms
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CD8-Positive T-Lymphocytes / immunology
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CD8-Positive T-Lymphocytes / metabolism*
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Carcinoma, Renal Cell / immunology
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Carcinoma, Renal Cell / metabolism*
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Carcinoma, Renal Cell / pathology
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Case-Control Studies
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Cell Cycle
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Cell Survival
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Chromium Isotopes
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Cyclin-Dependent Kinase Inhibitor p27
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E2F4 Transcription Factor / metabolism
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Enzyme-Linked Immunosorbent Assay
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Flow Cytometry
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Gene Expression Regulation, Neoplastic
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Humans
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Inhibitor of Differentiation Protein 2 / metabolism
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Intracellular Signaling Peptides and Proteins / metabolism
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Janus Kinase 3 / metabolism*
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Kidney Neoplasms / immunology
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Kidney Neoplasms / metabolism*
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Kidney Neoplasms / pathology
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Lymphocyte Culture Test, Mixed
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Microscopy, Confocal
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STAT5 Transcription Factor / metabolism*
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STAT6 Transcription Factor / metabolism*
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Signal Transduction
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Tumor Cells, Cultured
Substances
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CDKN1B protein, human
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Chromium Isotopes
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E2F4 Transcription Factor
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E2F4 protein, human
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ID2 protein, human
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Inhibitor of Differentiation Protein 2
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Intracellular Signaling Peptides and Proteins
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STAT5 Transcription Factor
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STAT6 Transcription Factor
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STAT6 protein, human
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Cyclin-Dependent Kinase Inhibitor p27
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JAK3 protein, human
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Janus Kinase 3