Force-dependent trans-endocytosis by breast cancer cells depletes costimulatory receptor CD80 and attenuates T cell activation.,Biosensors and Bioelectronics

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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

Department of Mechanical Engineering, Johns Hopkins University, MD, 21218, USA; Center for Cell Dynamics, Johns Hopkins University, MD, 21218, USA; Institute for NanoBioTechnology, Johns Hopkins University, MD, 21218, USA.
Department of Physics & Astronomy, Johns Hopkins University, MD, 21218, USA.
Department of Biophysics and Biophysical Chemistry, Johns Hopkins School of Medicine, Baltimore, MD, 21205, USA; Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, 21218, USA; Howard Hughes Medical Institute, Baltimore, MD, 21205, USA; Division of Nano-Bioengineering, Incheon National University, Incheon, 22012, South Korea.
Department of Biophysics and Biophysical Chemistry, Johns Hopkins School of Medicine, Baltimore, MD, 21205, USA.
Division of Biological Science, University of California, San Diego, CA, 92093, USA.
Department of Mechanical Engineering, Johns Hopkins University, MD, 21218, USA.
Department of Biophysics and Biophysical Chemistry, Johns Hopkins School of Medicine, Baltimore, MD, 21205, USA; Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, 21218, USA; Howard Hughes Medical Institute, Baltimore, MD, 21205, USA.

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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