Department of Medical Oncology, School of Cancer and Enabling Sciences, The University of Manchester, Manchester Academic Health Science Centre, Wilmslow Road, Manchester, UK.
Clin Immunol. 2011 Jan;138(1):85-96. doi: 10.1016/j.clim.2010.09.011. Epub 2010 Nov 5.
Cytotoxic T Lymphocyte Antigen 4 (CTLA4) blockade has shown antitumor activity against common cancers. However, the exact mechanism of immune mediation by anti-CTLA4 remains to be elucidated. Further understanding of how CTLA4 blockade with tremelimumab mediates immune responses may allow a more effective selection of responsive patients. Our results show that tremelimumab enhanced the proliferative response of T effector cells (Teff) upon TCR stimulation, and abrogated Treg suppressive ability. In the presence of tremelimumab, frequencies of IL-2-secreting CD4(+) T cells and IFN-γ-secreting CD4(+) and CD8(+) T cells were increased in response to polyclonal activation and tumor antigens. Importantly, Treg frequency was not reduced in the presence of tremelimumab, and expanded Tregs in cancer patients treated with tremelimumab expressed FoxP3 with no IL-2 release, confirming them as bona fide Tregs. Taken together, this data indicates that tremelimumab induces immune responses mainly by direct activation of Teff rather than by affecting Tregs.
细胞毒性 T 淋巴细胞相关抗原 4（CTLA4）阻断已显示出针对常见癌症的抗肿瘤活性。然而，抗 CTLA4 免疫介导的确切机制仍有待阐明。进一步了解 tremelimumab 如何通过 CTLA4 阻断来介导免疫反应，可能有助于更有效地选择有反应的患者。我们的结果表明，tremelimumab 增强了 TCR 刺激下 T 效应细胞（Teff）的增殖反应，并消除了 Treg 的抑制能力。在 tremelimumab 存在的情况下，对多克隆激活和肿瘤抗原的反应中，分泌 IL-2 的 CD4(+)T 细胞以及分泌 IFN-γ 的 CD4(+)和 CD8(+)T 细胞的频率增加。重要的是，在 tremelimumab 存在的情况下，Treg 的频率并未降低，并且接受 tremelimumab 治疗的癌症患者中扩增的 Treg 表达 FoxP3 而不释放 IL-2，证实它们是真正的 Treg。综上所述，这些数据表明，tremelimumab 主要通过直接激活 Teff 而不是通过影响 Treg 来诱导免疫反应。
