Abstract
Cytotoxic T Lymphocyte Antigen 4 (CTLA4) blockade has shown antitumor activity against common cancers. However, the exact mechanism of immune mediation by anti-CTLA4 remains to be elucidated. Further understanding of how CTLA4 blockade with tremelimumab mediates immune responses may allow a more effective selection of responsive patients. Our results show that tremelimumab enhanced the proliferative response of T effector cells (Teff) upon TCR stimulation, and abrogated Treg suppressive ability. In the presence of tremelimumab, frequencies of IL-2-secreting CD4(+) T cells and IFN-γ-secreting CD4(+) and CD8(+) T cells were increased in response to polyclonal activation and tumor antigens. Importantly, Treg frequency was not reduced in the presence of tremelimumab, and expanded Tregs in cancer patients treated with tremelimumab expressed FoxP3 with no IL-2 release, confirming them as bona fide Tregs. Taken together, this data indicates that tremelimumab induces immune responses mainly by direct activation of Teff rather than by affecting Tregs.
Copyright © 2010 Elsevier Inc. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antibodies, Monoclonal / pharmacology*
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Antibodies, Monoclonal / therapeutic use
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Antibodies, Monoclonal, Humanized
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CD4-Positive T-Lymphocytes / cytology
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CD4-Positive T-Lymphocytes / drug effects
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CD4-Positive T-Lymphocytes / immunology
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CD4-Positive T-Lymphocytes / metabolism
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CD8-Positive T-Lymphocytes / cytology
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CD8-Positive T-Lymphocytes / drug effects
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CD8-Positive T-Lymphocytes / immunology
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CD8-Positive T-Lymphocytes / metabolism
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Carcinoembryonic Antigen / immunology
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Cell Count
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Cell Proliferation / drug effects
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Forkhead Transcription Factors / metabolism
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Humans
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Immune Tolerance / drug effects
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Immune Tolerance / immunology
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Immunity, Cellular / drug effects*
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Immunity, Cellular / immunology
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Interferon-gamma / metabolism
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Interleukin-2 / metabolism
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Interleukin-2 Receptor alpha Subunit / metabolism
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Leukocytes, Mononuclear / cytology
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Leukocytes, Mononuclear / drug effects
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Leukocytes, Mononuclear / immunology
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Leukocytes, Mononuclear / metabolism
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Lymphocyte Activation / drug effects*
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Lymphocyte Activation / immunology
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Membrane Glycoproteins / immunology
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Neoplasms / drug therapy
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Neoplasms / immunology
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T-Lymphocyte Subsets / cytology
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T-Lymphocyte Subsets / drug effects*
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T-Lymphocyte Subsets / immunology
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T-Lymphocyte Subsets / metabolism
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T-Lymphocytes / cytology
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T-Lymphocytes / drug effects
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T-Lymphocytes / immunology
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T-Lymphocytes, Regulatory / cytology
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T-Lymphocytes, Regulatory / drug effects*
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T-Lymphocytes, Regulatory / immunology
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T-Lymphocytes, Regulatory / metabolism
Substances
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Antibodies, Monoclonal
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Antibodies, Monoclonal, Humanized
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Carcinoembryonic Antigen
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FOXP3 protein, human
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Forkhead Transcription Factors
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IL2RA protein, human
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Interleukin-2
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Interleukin-2 Receptor alpha Subunit
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Membrane Glycoproteins
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trophoblastic glycoprotein 5T4, human
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Interferon-gamma
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tremelimumab