Force-dependent trans-endocytosis by breast cancer cells depletes costimulatory receptor CD80 and attenuates T cell activation.
Force-dependent trans-endocytosis by breast cancer cells depletes costimulatory receptor CD80 and attenuates T cell activation.
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DOI：
10.1016/j.bios.2020.112389
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发表时间：
2020-10-01
影响因子：
12.6
通讯作者：
Chen Y
中科院分区：
文献类型：
--
作者：
Park S;Shi Y;Kim BC;Jo MH;Cruz LO;Gou Z;Ha T;Lu LF;Reich DH;Chen Y
在这项研究中，我们研究了细胞毒性T淋巴细胞相关蛋白4（CTLA-4）和CD 80之间的生物物理相互作用。CTLA-4是免疫抑制中的关键分子，而CD 80是促进T细胞活化的共刺激受体。我们观察到，在乳腺癌细胞和抗原呈递细胞（APC）之间建立细胞-细胞接触后，在乳腺癌细胞上表达的CTLA-4与在APC上表达的CD 80结合，并经历反式内吞作用以消耗CD 80。力测量和活细胞成像显示，在与CD 80结合时，由乳腺癌细胞产生并通过CTLA-4传递的力足够强，足以从APC表面置换CD 80，以被乳腺癌细胞内化。我们进一步证明，由于CD 80的力依赖性反式内吞作用，APC激活T细胞的能力显著减弱。此外，抑制癌细胞中的力产生将增加APC的T细胞活化能力。我们的研究结果提供了乳腺癌患者中常见的免疫抑制背后的可能机制，并可能导致通过抑制力生成途径来恢复抗肿瘤免疫的新策略。
In this study, we investigated the biophysical interaction between cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and CD80. CTLA-4 is a key molecule in immunosuppression, and CD80 is a costimulatory receptor promoting T cell activation. We observed that after cell-cell contact was established between breast cancer cells and antigen presenting cells (APCs), CTLA-4 expressed on the breast cancer cells bind to CD80 expressed on the APCs, and underwent trans-endocytosis to deplete CD80. Force measurement and live cell imaging revealed that upon binding to CD80, forces generated by breast cancer cells and transmitted via CTLA-4 were sufficiently strong to displace CD80 from the surface of APCs to be internalized by breast cancer cells. We further demonstrated that because of the force-dependent trans-endocytosis of CD80, the capacity of APCs to activate T cells was significantly attenuated. Furthermore, inhibiting force generation in cancer cells would increase the T cell activating capacity of APCs. Our results provide a possible mechanism behind the immunosuppression commonly seen in breast cancer patients, and may lead to a new strategy to restore anti-tumor immunity by inhibiting pathways of force-generation.
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DOI：
10.4049/jimmunol.1401876
发表时间：
2015-03-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Hou TZ;Qureshi OS;Wang CJ;Baker J;Young SP;Walker LS;Sansom DM
通讯作者：
Sansom DM
影响因子：
2.9
作者：
Guo, Jinhong;Chen, Liang;Kang, Yuejun
通讯作者：
Kang, Yuejun
影响因子：
7.4
作者：
Laurent S;Queirolo P;Boero S;Salvi S;Piccioli P;Boccardo S;Minghelli S;Morabito A;Fontana V;Pietra G;Carrega P;Ferrari N;Tosetti F;Chang LJ;Mingari MC;Ferlazzo G;Poggi A;Pistillo MP
通讯作者：
Pistillo MP
影响因子：
82.9
作者：
Choi, Je-Min;Ahn, Mi-Hyun;Lee, Sang-Kyou
通讯作者：
Lee, Sang-Kyou
影响因子：
4.8
作者：
Kovács, M;Tóth, J;Sellers, JR
通讯作者：
Sellers, JR