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

Seungman Park; Yu Shi; Byoung Choul Kim; Myung Hyun Jo; Leilani O Cruz; Zheming Gou; Taekjip Ha; Li-Fan Lu; Daniel H Reich; Yun Chen

doi:10.1016/j.bios.2020.112389

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

Biosens Bioelectron. 2020 Oct 1:165:112389. doi: 10.1016/j.bios.2020.112389. Epub 2020 Jun 17.

Authors

Seungman Park¹, Yu Shi², Byoung Choul Kim³, Myung Hyun Jo⁴, Leilani O Cruz⁵, Zheming Gou⁶, Taekjip Ha⁷, Li-Fan Lu⁵, Daniel H Reich², Yun Chen⁸

Affiliations

¹ 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.
² Department of Physics & Astronomy, Johns Hopkins University, MD, 21218, USA.
³ 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.
⁴ Department of Biophysics and Biophysical Chemistry, Johns Hopkins School of Medicine, Baltimore, MD, 21205, USA.
⁵ Division of Biological Science, University of California, San Diego, CA, 92093, USA.
⁶ Department of Mechanical Engineering, Johns Hopkins University, MD, 21218, USA.
⁷ 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.
⁸ 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. Electronic address: [email protected].

Abstract

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.

MeSH terms

B7-2 Antigen
Biosensing Techniques*
Breast Neoplasms*
CD28 Antigens
Endocytosis
Humans
Lymphocyte Activation
T-Lymphocytes

Substances

B7-2 Antigen
CD28 Antigens

Abstract

MeSH terms

Substances

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