Fc-dependent depletion of tumor-infiltrating regulatory T cells co-defines the efficacy of anti-CTLA-4 therapy against melanoma

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 activ...

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Veröffentlicht in:The Journal of experimental medicine Jg. 210; H. 9; S. 1695
Hauptverfasser: Simpson, Tyler R, Li, Fubin, Montalvo-Ortiz, Welby, Sepulveda, Manuel A, Bergerhoff, Katharina, Arce, Frederick, Roddie, Claire, Henry, Jake Y, Yagita, Hideo, Wolchok, Jedd D, Peggs, Karl S, Ravetch, Jeffrey V, Allison, James P, Quezada, Sergio A
Format: Journal Article
Sprache:Englisch
Veröffentlicht: United States 26.08.2013
Schlagworte:
Animals
Antibodies, Blocking - pharmacology
Antibodies, Blocking - therapeutic use
CD11b Antigen - metabolism
CD4 Antigens - metabolism
CD8-Positive T-Lymphocytes - drug effects
CD8-Positive T-Lymphocytes - immunology
Cell Membrane - drug effects
Cell Membrane - metabolism
Clone Cells
CTLA-4 Antigen - antagonists & inhibitors
Fas Ligand Protein - metabolism
Granulocyte-Macrophage Colony-Stimulating Factor - therapeutic use
Lymph Nodes - drug effects
Lymph Nodes - immunology
Lymph Nodes - pathology
Lymphocyte Count
Lymphocyte Depletion
Lymphocytes, Tumor-Infiltrating - drug effects
Lymphocytes, Tumor-Infiltrating - immunology
Lymphocytes, Tumor-Infiltrating - pathology
Melanoma - immunology
Melanoma - pathology
Melanoma - prevention & control
Melanoma - therapy
Mice
Mice, Inbred C57BL
Phagocytes - drug effects
Phagocytes - immunology
Receptors, IgG - metabolism
Signal Transduction - drug effects
Signal Transduction - immunology
T-Lymphocytes, Regulatory - drug effects
T-Lymphocytes, Regulatory - immunology
TNF-Related Apoptosis-Inducing Ligand - metabolism
Treatment Outcome
Tumor Microenvironment - drug effects
Tumor Microenvironment - immunology
ISSN:1540-9538, 1540-9538
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Zusammenfassung: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.
Bibliographie:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ISSN:1540-9538
1540-9538
DOI:10.1084/jem.20130579