期刊
JOURNAL OF EXPERIMENTAL MEDICINE
卷 210, 期 9, 页码 1695-1710出版社
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20130579
关键词
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资金
- Canadian Institutes of Health Research Doctoral Research Award
- Cancer Research UK Career Development Fellowship
- Cancer Research Institute Investigator Award
- Leukaemia Lymphoma Research UK
- Cancer Research UK [12100] Funding Source: researchfish
- Medical Research Council [G0902016] Funding Source: researchfish
- MRC [G0902016] Funding Source: UKRI
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 Fc gamma 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.
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