Abstract
Kidney cancer is a devastating disease; however, biological therapies have achieved some limited success. The murine renal cancer Renca has been used as a model for developing new preclinical approaches to the treatment of renal cell carcinoma. Successful cytokine-based approaches require CD8(+) T cells, but the exact mechanisms by which T cells mediate therapeutic benefit have not been completely identified. After successful biological therapy of Renca in BALB/c mice, we generated CTLs in vitro using mixed lymphocyte tumor cultures. These CTL mediated tumor-specific H-2K(d)-restricted lysis and production of IFN-gamma, TNF-alpha, and Fas ligand (FasL) in response to Renca. CTL used both granule- and FasL-mediated mechanisms to lyse Renca, although granule-mediated killing was the predominant lytic mechanism in vitro. The cytokines IFN-gamma and TNF-alpha increased the sensitivity of Renca cells to CTL lysis by both granule- and FasL-mediated death pathways. Adoptive transfer of these anti-Renca CTL into tumor-bearing mice cured most mice of established experimental pulmonary metastases, and successfully treated mice were immune to tumor rechallenge. Interestingly, we were able to establish Renca-specific CTL from mice gene targeted for perforin (pfp(-/-)) mice. Although these pfp(-/-) CTL showed reduced cytotoxic activity against Renca, their IFN-gamma production in the presence of Renca targets was equivalent to that of wild-type CTL, and adoptive transfer of pfp(-/-) CTL was as efficient as wild-type CTL in causing regression of established Renca pulmonary metastases. Therefore, although granule-mediated killing is of paramount importance for CTL-mediated lysis in vitro, some major in vivo effector mechanisms clearly are independent of perforin.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Antineoplastic Agents / toxicity
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Apoptosis / genetics
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Apoptosis / immunology
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Apoptosis Regulatory Proteins
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Carcinoma, Renal Cell / immunology
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Carcinoma, Renal Cell / pathology
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Carcinoma, Renal Cell / therapy*
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Cell Line, Transformed
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Cytotoxicity, Immunologic* / genetics
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Epitopes, T-Lymphocyte / administration & dosage
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Epitopes, T-Lymphocyte / immunology*
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Fas Ligand Protein
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Immunotherapy, Adoptive / methods
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Intercellular Adhesion Molecule-1 / metabolism
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Intercellular Adhesion Molecule-1 / physiology
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Kidney Neoplasms / immunology
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Kidney Neoplasms / pathology
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Kidney Neoplasms / therapy*
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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 / secondary
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Lung Neoplasms / therapy
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Lymphocyte Activation / genetics
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Lymphocyte Function-Associated Antigen-1 / metabolism
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Lymphocyte Function-Associated Antigen-1 / physiology
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Melanoma, Experimental / immunology
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Membrane Glycoproteins / biosynthesis
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Membrane Glycoproteins / deficiency*
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Membrane Glycoproteins / genetics
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Membrane Glycoproteins / metabolism
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Membrane Glycoproteins / toxicity*
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Mice
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Mice, Inbred BALB C
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Mice, Inbred C3H
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Mice, Inbred C57BL
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Mice, Inbred DBA
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Mice, Knockout
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Neoplasm Transplantation
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Perforin
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Pore Forming Cytotoxic Proteins
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T-Lymphocytes, Cytotoxic / immunology*
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T-Lymphocytes, Cytotoxic / transplantation
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TNF-Related Apoptosis-Inducing Ligand
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Tumor Cells, Cultured
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Tumor Necrosis Factor-alpha / toxicity
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fas Receptor / metabolism
Substances
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Antineoplastic Agents
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Apoptosis Regulatory Proteins
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Epitopes, T-Lymphocyte
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Fas Ligand Protein
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Fasl protein, mouse
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Ligands
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Lymphocyte Function-Associated Antigen-1
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Membrane Glycoproteins
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Pore Forming Cytotoxic Proteins
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TNF-Related Apoptosis-Inducing Ligand
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Tnfsf10 protein, mouse
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Tumor Necrosis Factor-alpha
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fas Receptor
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Perforin
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Intercellular Adhesion Molecule-1