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

• Published in: The Journal of experimental medicine Vol. 210; no. 9; pp. 1695 - 1710
• Main Authors: 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
• Language: English
• Published: United States The Rockefeller University Press 26.08.2013
• Subjects: 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: 0022-1007; 1540-9538; 1540-9538
• DOI: 10.1084/jem.20130579

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.