Abstract
In the present report, we have investigated TRAIL/APO2 ligand (APO2L) expression, regulation, and function in human lung carcinoma tumor-infiltrating lymphocytes. Using a panel of non-small cell lung carcinoma cell lines, we first showed that most of them expressed TRAIL-R1/DR4, TRAIL-R2/DR5, but not TRAIL-R3/DcR1 and TRAIL-R4/DcR2, and were susceptible to APO2L/TRAIL-induced cell death. Two APO2L/TRAIL-sensitive tumor cell lines (MHC class I(+)/II(+) or I(+)/II(-)) were selected and specific CD4(+) HLA-DR- or CD8(+) HLA-A2-restricted CTL clones were respectively isolated from autologous tumor-infiltrating lymphocytes. Interestingly, although the established T cell clones did not constitutively express detectable levels of APO2L/TRAIL, engagement of their TCR via activation with specific tumor cells selectively induced profound APO2L/TRAIL expression on the CD4(+), but not on the CD8(+), CTL clones. Furthermore, as opposed to the CD8(+) CTL clone which mainly used granule exocytosis pathway, the CD4(+) CTL clone lysed the specific target via both perforin/granzymes and APO2L/TRAIL-mediated mechanisms. The latter cytotoxicity correlated with APO2L/TRAIL expression and was significantly enhanced in the presence of IFN-alpha. More interestingly, in vivo studies performed in SCID/nonobese diabetic mice transplanted with autologous tumor and transferred with the specific CD4(+) CTL clone in combination with IFN-alpha resulted in an important APO2L/TRAIL-mediated tumor growth inhibition, which was prohibited by soluble TRAIL-R2. Our findings suggest that APO2L/TRAIL, specifically induced by autologous tumor and up-regulated by IFN-alpha, may be a key mediator of tumor-specific CD4(+) CTL-mediated cell death and point to a potent role of this T cell subset in tumor growth control.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adoptive Transfer
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Aged
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Animals
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Apoptosis Regulatory Proteins
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CD4-Positive T-Lymphocytes / immunology
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CD4-Positive T-Lymphocytes / metabolism*
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CD4-Positive T-Lymphocytes / transplantation
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Carcinoma, Non-Small-Cell Lung / immunology*
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Carcinoma, Non-Small-Cell Lung / pathology
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Carcinoma, Non-Small-Cell Lung / prevention & control
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Clone Cells / immunology
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Clone Cells / metabolism
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Clone Cells / transplantation
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Cytotoxicity, Immunologic* / immunology
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Female
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Growth Inhibitors / administration & dosage
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Growth Inhibitors / toxicity
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Humans
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Injections, Intralesional
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Interferon-alpha / administration & dosage
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Interferon-alpha / physiology*
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Interferon-alpha / toxicity
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Ligands
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Lung Neoplasms / immunology*
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Lung Neoplasms / pathology
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Lung Neoplasms / prevention & control
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Lymphocyte Activation / immunology
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Lymphocytes, Tumor-Infiltrating / immunology
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Lymphocytes, Tumor-Infiltrating / metabolism*
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Male
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Membrane Glycoproteins / biosynthesis*
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Membrane Glycoproteins / physiology
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Membrane Glycoproteins / toxicity*
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Mice
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Mice, Inbred NOD
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Mice, Nude
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Mice, SCID
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Middle Aged
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T-Lymphocytes, Cytotoxic / immunology
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T-Lymphocytes, Cytotoxic / metabolism
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T-Lymphocytes, Cytotoxic / transplantation
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T-Lymphocytes, Regulatory / immunology
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T-Lymphocytes, Regulatory / metabolism
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T-Lymphocytes, Regulatory / transplantation
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TNF-Related Apoptosis-Inducing Ligand
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Tumor Cells, Cultured / immunology
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Tumor Cells, Cultured / metabolism
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Tumor Cells, Cultured / transplantation
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Tumor Necrosis Factor-alpha / biosynthesis*
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Tumor Necrosis Factor-alpha / physiology
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Tumor Necrosis Factor-alpha / toxicity*
Substances
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Apoptosis Regulatory Proteins
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Growth Inhibitors
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Interferon-alpha
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Ligands
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Membrane Glycoproteins
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TNF-Related Apoptosis-Inducing Ligand
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TNFSF10 protein, human
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Tnfsf10 protein, mouse
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Tumor Necrosis Factor-alpha