Fc-dependent depletion of tumor-infiltrating regulatory T cells co-defines the efficacy of anti-CTLA-4 therapy against melanoma.
Fc-dependent depletion of tumor-infiltrating regulatory T cells co-defines the efficacy of anti-CTLA-4 therapy against melanoma.
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DOI：
10.1084/jem.20130579
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发表时间：
2013-08-26
期刊：
影响因子：
--
通讯作者：
Quezada SA
中科院分区：
文献类型：
--
作者：
Simpson TR;Li F;Montalvo-Ortiz W;Sepulveda MA;Bergerhoff K;Arce F;Roddie C;Henry JY;Yagita H;Wolchok JD;Peggs KS;Ravetch JV;Allison JP;Quezada SA
抗CTLA - 4抗体以一种依赖于肿瘤微环境中表达Fcγ受体的巨噬细胞存在的方式，诱导肿瘤病灶内调节性T细胞（T reg细胞）的选择性耗竭。
用针对细胞毒性T淋巴细胞相关抗原4（CTLA - 4，一种由T淋巴细胞表达的抑制性受体）的单克隆抗体进行治疗，已成为治疗转移性黑色素瘤的一种有效疗法。尽管存在争议，但目前的模型倾向于一种作用机制，即阻断CTLA - 4对效应T细胞（T eff）和调节性T细胞（T reg）的抑制活性，从而导致能够诱导肿瘤消退的抗肿瘤效应T细胞活性增强。然而，我们证明抗CTLA - 4抗体对T reg细胞区室的作用是通过肿瘤病灶内T reg细胞的选择性耗竭来介导的。重要的是，T reg细胞的耗竭依赖于肿瘤微环境中表达Fcγ受体的巨噬细胞的存在，这表明T reg细胞是以一种依赖环境的方式在反式作用中被耗竭的。我们的结果进一步揭示了基于抗CTLA - 4的癌症免疫疗法的作用机制，并阐明了局部肿瘤环境的特定特征对基于抗体的免疫调节疗法最终结果的重要性。
Anti–CTLA-4 antibody induces selective depletion of T reg cells within tumor lesions in a manner that is dependent on the presence of Fc gamma receptor-expressing macrophages within the tumor microenvironment. 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.
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DOI：
10.1056/nejmoa1003466
发表时间：
2010-08-19
期刊：
The New England journal of medicine
影响因子：
--
作者：
Hodi FS;O'Day SJ;McDermott DF;Weber RW;Sosman JA;Haanen JB;Gonzalez R;Robert C;Schadendorf D;Hassel JC;Akerley W;van den Eertwegh AJ;Lutzky J;Lorigan P;Vaubel JM;Linette GP;Hogg D;Ottensmeier CH;Lebbé C;Peschel C;Quirt I;Clark JI;Wolchok JD;Weber JS;Tian J;Yellin MJ;Nichol GM;Hoos A;Urba WJ
通讯作者：
Urba WJ
影响因子：
11.2
作者：
Chen, Aoshuang;Liu, Shanrong;Zheng, Guoxing
通讯作者：
Zheng, Guoxing
影响因子：
20.3
作者：
Kavanagh, Brian;O'Brien, Shaun;Fong, Lawrence
通讯作者：
Fong, Lawrence
影响因子：
20.3
作者：
Li, Yongqing;Yee, Cassian
通讯作者：
Yee, Cassian
DOI：
10.1073/pnas.0806075105
发表时间：
2008-09-30
影响因子：
11.1
作者：
Liakou, Chrysoula I.;Kamat, Ashish;Sharma, Padmanee
通讯作者：
Sharma, Padmanee