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Force-dependent trans-endocytosis by breast cancer cells depletes costimulatory receptor CD80 and attenuates T cell activation.
Biosensors and Bioelectronics ( IF 10.7 ) Pub Date : 2020-06-17 , DOI: 10.1016/j.bios.2020.112389
Seungman Park 1 , Yu Shi 2 , Byoung Choul Kim 3 , Myung Hyun Jo 4 , Leilani O Cruz 5 , Zheming Gou 6 , Taekjip Ha 7 , Li-Fan Lu 5 , Daniel H Reich 2 , Yun Chen 1
Affiliation  

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.



中文翻译:

乳腺癌细胞的力依赖性跨内吞作用耗尽了共刺激受体CD80,并减弱了T细胞活化。

在这项研究中,我们调查了细胞毒性T淋巴细胞相关蛋白4(CTLA-4)和CD80之间的生物物理相互作用。CTLA-4是免疫抑制的关键分子,而CD80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)之间建立了细胞接触之后,乳腺癌细胞上表达的CTLA-4与APC上表达的CD80结合,并进行内吞吞噬以耗尽CD80。力测量和活细胞成像显示,与CD80结合后,由乳腺癌细胞产生并通过CTLA-4传递的力足以将CD80从APC的表面置换,从而被乳腺癌细胞内化。我们进一步证明,由于CD80的作用力依赖于跨胞吞作用,APC激活T细胞的能力明显减弱。此外,抑制癌细胞中的力产生将增加APC的T细胞活化能力。我们的结果提供了在乳腺癌患者中常见的免疫抑制背后的可能机制,并且可能导致通过抑制力量生成途径来恢复抗肿瘤免疫力的新策略。

更新日期:2020-06-27
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