Abstract
Treatment with monoclonal antibody specific for cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), an inhibitory receptor expressed by T lymphocytes, has emerged as an effective therapy for the treatment of metastatic melanoma. Although subject to debate, current models favor a mechanism of activity involving blockade of the inhibitory activity of CTLA-4 on both effector (T eff) and regulatory (T reg) T cells, resulting in enhanced antitumor effector T cell activity capable of inducing tumor regression. We demonstrate, however, that the activity of anti-CTLA-4 antibody on the T reg cell compartment is mediated via selective depletion of T reg cells within tumor lesions. Importantly, T reg cell depletion is dependent on the presence of Fcγ receptor-expressing macrophages within the tumor microenvironment, indicating that T reg cells are depleted in trans in a context-dependent manner. Our results reveal further mechanistic insight into the activity of anti-CTLA-4-based cancer immunotherapy, and illustrate the importance of specific features of the local tumor environment on the final outcome of antibody-based immunomodulatory therapies.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antibodies, Blocking / pharmacology
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Antibodies, Blocking / therapeutic use
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CD11b Antigen / metabolism
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CD4 Antigens / metabolism
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CD8-Positive T-Lymphocytes / drug effects
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CD8-Positive T-Lymphocytes / immunology
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CTLA-4 Antigen / antagonists & inhibitors*
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Cell Membrane / drug effects
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Cell Membrane / metabolism
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Clone Cells
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Fas Ligand Protein / metabolism
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Granulocyte-Macrophage Colony-Stimulating Factor / therapeutic use
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Lymph Nodes / drug effects
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Lymph Nodes / immunology
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Lymph Nodes / pathology
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Lymphocyte Count
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Lymphocyte Depletion*
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Lymphocytes, Tumor-Infiltrating / drug effects
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Lymphocytes, Tumor-Infiltrating / immunology*
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Lymphocytes, Tumor-Infiltrating / pathology
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Melanoma / immunology*
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Melanoma / pathology
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Melanoma / prevention & control
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Melanoma / therapy*
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Mice
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Mice, Inbred C57BL
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Phagocytes / drug effects
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Phagocytes / immunology
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Receptors, IgG / metabolism*
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Signal Transduction / drug effects
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Signal Transduction / immunology
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T-Lymphocytes, Regulatory / drug effects
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T-Lymphocytes, Regulatory / immunology*
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TNF-Related Apoptosis-Inducing Ligand / metabolism
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Treatment Outcome
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Tumor Microenvironment / drug effects
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Tumor Microenvironment / immunology
Substances
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Antibodies, Blocking
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CD11b Antigen
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CD4 Antigens
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CTLA-4 Antigen
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Fas Ligand Protein
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Fcgr4 protein, mouse
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Receptors, IgG
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TNF-Related Apoptosis-Inducing Ligand
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Granulocyte-Macrophage Colony-Stimulating Factor