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

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.

• Authors: Tyler R Simpson, Fubin Li, Welby Montalvo-Ortiz, Manuel A Sepulveda, Katharina Bergerhoff, Frederick Arce, Claire Roddie, Jake Y Henry, Hideo Yagita, Jedd D Wolchok, Karl S Peggs, Jeffrey V Ravetch, James P Allison, Sergio A Quezada
• Journal: The Journal of experimental medicine (J Exp Med) Vol. 210 Issue 9 Pg. 1695-710 (Aug 26 2013) ISSN: 1540-9538 [Electronic] United States
• PMID: 23897981 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Blocking
• CD11b Antigen
• CD4 Antigens
• CTLA-4 Antigen
• Fas Ligand Protein
• Fcgr4 protein, mouse
• Receptors, IgG
• TNF-Related Apoptosis-Inducing Ligand
• Granulocyte-Macrophage Colony-Stimulating Factor

Topics

• Animals
• Antibodies, Blocking (pharmacology, therapeutic use)
• CD11b Antigen (metabolism)
• CD4 Antigens (metabolism)
• CD8-Positive T-Lymphocytes (drug effects, immunology)
• CTLA-4 Antigen (antagonists & inhibitors)
• Cell Membrane (drug effects, metabolism)
• Clone Cells
• Fas Ligand Protein (metabolism)
• Granulocyte-Macrophage Colony-Stimulating Factor (therapeutic use)
• Lymph Nodes (drug effects, immunology, pathology)
• Lymphocyte Count
• Lymphocyte Depletion
• Lymphocytes, Tumor-Infiltrating (drug effects, immunology, pathology)
• Melanoma (immunology, pathology, prevention & control, therapy)
• Mice
• Mice, Inbred C57BL
• Phagocytes (drug effects, immunology)
• Receptors, IgG (metabolism)
• Signal Transduction (drug effects, immunology)
• T-Lymphocytes, Regulatory (drug effects, immunology)
• TNF-Related Apoptosis-Inducing Ligand (metabolism)
• Treatment Outcome
• Tumor Microenvironment (drug effects, immunology)