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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Vydáno v:	The Journal of experimental medicine Ročník 210; číslo 9; s. 1695
Hlavní autoři:	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
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	United States 26.08.2013
Témata:	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
On-line přístup:	Zjistit podrobnosti o přístupu
Tagy:	Přidat tag Žádné tagy, Buďte první, kdo vytvoří štítek k tomuto záznamu!

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.
AbstractList	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.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. 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.
Author	Quezada, Sergio A Arce, Frederick Ravetch, Jeffrey V Yagita, Hideo Peggs, Karl S Li, Fubin Allison, James P Bergerhoff, Katharina Sepulveda, Manuel A Roddie, Claire Montalvo-Ortiz, Welby Wolchok, Jedd D Simpson, Tyler R Henry, Jake Y
Author_xml	– sequence: 1 givenname: Tyler R surname: Simpson fullname: Simpson, Tyler R organization: Department of Immunology, M D Anderson Cancer Center, Houston, TX 77030, USA – sequence: 2 givenname: Fubin surname: Li fullname: Li, Fubin – sequence: 3 givenname: Welby surname: Montalvo-Ortiz fullname: Montalvo-Ortiz, Welby – sequence: 4 givenname: Manuel A surname: Sepulveda fullname: Sepulveda, Manuel A – sequence: 5 givenname: Katharina surname: Bergerhoff fullname: Bergerhoff, Katharina – sequence: 6 givenname: Frederick surname: Arce fullname: Arce, Frederick – sequence: 7 givenname: Claire surname: Roddie fullname: Roddie, Claire – sequence: 8 givenname: Jake Y surname: Henry fullname: Henry, Jake Y – sequence: 9 givenname: Hideo surname: Yagita fullname: Yagita, Hideo – sequence: 10 givenname: Jedd D surname: Wolchok fullname: Wolchok, Jedd D – sequence: 11 givenname: Karl S surname: Peggs fullname: Peggs, Karl S – sequence: 12 givenname: Jeffrey V surname: Ravetch fullname: Ravetch, Jeffrey V – sequence: 13 givenname: James P surname: Allison fullname: Allison, James P – sequence: 14 givenname: Sergio A surname: Quezada fullname: Quezada, Sergio A
BackLink	https://www.ncbi.nlm.nih.gov/pubmed/23897981$$D View this record in MEDLINE/PubMed
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Snippet	Treatment with monoclonal antibody specific for cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), an inhibitory receptor expressed by T lymphocytes, has...
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SubjectTerms	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
Title	Fc-dependent depletion of tumor-infiltrating regulatory T cells co-defines the efficacy of anti-CTLA-4 therapy against melanoma
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