Abstract
We have recently shown that effector T cells (T(E)) lacking either perforin or IFN-gamma are highly effective mediators of tumor regression. To rule out compensation by either mechanism, T(E) deficient in both perforin and IFN-gamma (perforin knockout (PKO)/IFN-gamma knockout (GKO)) were generated. The adoptive transfer of PKO/GKO T(E) mediated complete tumor regression and cured wild-type animals with established pulmonary metastases of the B16BL6-D5 (D5) melanoma cell line. PKO/GKO T(E) also mediated tumor regression in D5 tumor-bearing PKO, GKO, or PKO/GKO recipients, although in PKO/GKO recipients efficacy was reduced. PKO/GKO T(E) exhibited tumor-specific TNF-alpha production and cytotoxicity in a 24-h assay, which was blocked by the soluble TNFRII-human IgG fusion protein (TNFRII:Fc). Blocking TNF in vivo by administering soluble TNFR II fusion protein (TNFRII:Fc) significantly reduced the therapeutic efficacy of PKO/GKO, but not wild-type T(E). This study identifies perforin, IFN-gamma, and TNF as a critical triad of effector molecules that characterize therapeutic antitumor T cells. These insights could be used to monitor and potentially tune the immune response to cancer vaccines.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adoptive Transfer* / methods
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Animals
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Antigens, CD / administration & dosage
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Antigens, CD / immunology
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Antigens, CD / metabolism
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Binding, Competitive / genetics
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Binding, Competitive / immunology
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Cancer Vaccines / administration & dosage
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Cancer Vaccines / genetics
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Cells, Cultured
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Cytotoxicity, Immunologic / genetics
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Epitopes, T-Lymphocyte / immunology
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Immunoglobulin Fc Fragments / administration & dosage
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Immunoglobulin Fc Fragments / metabolism
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Injections, Intraperitoneal
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Injections, Subcutaneous
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Interferon-gamma / deficiency*
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Interferon-gamma / genetics
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Lung Neoplasms / immunology
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Lung Neoplasms / prevention & control
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Lung Neoplasms / secondary
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Melanoma, Experimental / genetics
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Melanoma, Experimental / immunology*
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Melanoma, Experimental / therapy*
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Membrane Glycoproteins / deficiency*
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Membrane Glycoproteins / genetics
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Perforin
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Pore Forming Cytotoxic Proteins
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Receptors, Tumor Necrosis Factor / administration & dosage
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Receptors, Tumor Necrosis Factor / immunology
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Receptors, Tumor Necrosis Factor / metabolism
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Receptors, Tumor Necrosis Factor, Type II
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Recombinant Fusion Proteins / immunology
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Recombinant Fusion Proteins / metabolism
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T-Lymphocyte Subsets / immunology
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T-Lymphocyte Subsets / metabolism
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T-Lymphocyte Subsets / 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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Tumor Cells, Cultured
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Tumor Necrosis Factor-alpha / biosynthesis
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Tumor Necrosis Factor-alpha / physiology*
Substances
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Antigens, CD
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Cancer Vaccines
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Epitopes, T-Lymphocyte
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Immunoglobulin Fc Fragments
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Membrane Glycoproteins
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Pore Forming Cytotoxic Proteins
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Receptors, Tumor Necrosis Factor
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Receptors, Tumor Necrosis Factor, Type II
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Recombinant Fusion Proteins
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Tumor Necrosis Factor-alpha
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Perforin
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Interferon-gamma