Abstract
Stimulation of 4-1BB (CD137) was shown to produce strong anticancer effects in vivo. In contrast, 4-1BB-deficient (4-1BB(-/-)) B6 mice are remarkably resistant to tumor growth. We set out to determine the mechanisms involved in these seemingly contradictory observations. We found that the therapeutic effects of 4-1BB triggering were mainly dependent on CD8(+) T cells and partially on NK cells, whereas CD8(+) T and NK cells were equally needed to suppress tumor growth in 4-1BB(-/-) mice. Cellular analysis showed that the frequency and number of NK cells in the spleen and bone marrow were decreased by 4-1BB triggering but were increased in the absence of 4-1BB signaling in tumor-challenged mice. The 4-1BB-mediated downregulation of NK cell development was primarily dependent on IFN-gamma, which was produced by peripheral CD8(+) T and NK cells. The suppression of NK cell development by 4-1BB-mediated IFN-gamma production occurred in the bone marrow. As 4-1BB signaling increased in the periphery, more CD8(+) T cells but fewer NK cells contributed to the antitumor immunity. As 4-1BB signaling decreased, more NK cells participated in the antitumor immunity. We conclude that 4-1BB signaling results in a shift of the dominant type of immune cell in antitumor immunity from the innate NK cell to the adaptive CD8(+) T cell and that the level of IFN-gamma is critical for this 4-1BB-mediated shift.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenocarcinoma / immunology
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Adenocarcinoma / pathology
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Adenocarcinoma / prevention & control
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Animals
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Bone Marrow Cells / immunology
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Bone Marrow Cells / metabolism
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Bone Marrow Cells / pathology
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CD8-Positive T-Lymphocytes / immunology
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CD8-Positive T-Lymphocytes / metabolism
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CD8-Positive T-Lymphocytes / pathology
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Cell Differentiation / genetics
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Cell Differentiation / immunology*
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Cell Line, Tumor
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Colonic Neoplasms / immunology
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Colonic Neoplasms / pathology
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Colonic Neoplasms / prevention & control
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Down-Regulation / genetics
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Down-Regulation / immunology*
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Female
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Immunity, Innate / genetics
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Immunodominant Epitopes / genetics
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Immunodominant Epitopes / immunology
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Interferon-gamma / deficiency
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Interferon-gamma / genetics
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Interferon-gamma / physiology*
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Kidney Neoplasms / immunology
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Kidney Neoplasms / pathology
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Kidney Neoplasms / prevention & control
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Killer Cells, Natural / immunology*
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Killer Cells, Natural / metabolism
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Killer Cells, Natural / pathology
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Mice
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Mice, Inbred BALB C
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Mice, Inbred C57BL
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Mice, Knockout
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Signal Transduction / genetics
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Signal Transduction / immunology*
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Thymoma / immunology
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Thymoma / pathology
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Thymoma / prevention & control
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Tumor Necrosis Factor Receptor Superfamily, Member 9 / deficiency
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Tumor Necrosis Factor Receptor Superfamily, Member 9 / genetics
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Tumor Necrosis Factor Receptor Superfamily, Member 9 / physiology*
Substances
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Immunodominant Epitopes
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Tumor Necrosis Factor Receptor Superfamily, Member 9
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Interferon-gamma