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Cellular vesicles expressing PD-1-blocking scFv reinvigorate T cell immunity against cancer

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Abstract

Cancer cells aberrantly express immunosuppressive checkpoint ligands and produce certain metabolites that lead to T cell exhaustion. Immune checkpoint blockade (ICB) therapy that reinvigorates exhausted T cells have achieved impressive response in clinical cancer treatment. However, the limited clinical response rate and off-tumor toxicities restrict ICB therapy. Herein, cellular vesicles displaying anti-programmed cell death-1 (PD-1) single-chain variable fragment antibody (aPD-1-scFv) were prepared to reinvigorate T cell immunity to counteract cancer. The nanovesicles displaying aPD-1-scFv (aPD-1-scFv NVs) could enhance the anti-tumor activation of T cells through PD-1 blockade. Furthermore, NVs loading the A2a adenosine receptor (A2aR) antagonist CPI-444 assisted T cells to antagonize adenosine, an immunosuppressive metabolite produced by cancer cells. Hence, CPI-444 loaded aPD-1-scFv NVs could intensively increase the density and activity of tumor infiltrating T cells, directly restraining tumor progress and metastasis.

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Acknowledgements

This work was supported by grants from the National Natural Science Foundation of China (No. 31971268), the Natural Science Foundation of Guangdong Province (No. 2020A1515010802), Guangdong Basic and Applied Basic Research Foundation (No. 2020A1515110166), Shenzhen Excellent Science and Technology Innovation Talent Training Project (Excellent Youth Project, No. RCYX20200714114643121), Science, Technology & Innovation Commission of Shenzhen Municipality (No. JCYJ20200109142610136), Basic Research Program of Shenzhen (No. JCYJ20180507181654186), Health System Scientific Research Project of Shenzhen Guangming District Science and Innovation Bureau (Nos. 2020R01073, and 2020R01061), Special Fund for Economic Development of Guangming District, Shenzhen (No. 2021R01128), University of Chinese Academy of Sciences—Shenzhen Hospital Research Funding (No. HRF-2020004), the Fundamental Research Funds for the Central Universities (No. 19lgzd45), Disciplinary Construction of Posts of Zhujiang Scholars (No. 4SG21005G), and Discipline Construction Project of Guangdong Medical University (No. 4SG21008G).

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  1. Tianyuan Xue, Zhirang Zhang, and Tianliang Fang contributed equally to this work.

Authors and Affiliations

  1. Department of Pharmacology, Molecular Cancer Research Center, School of Medicine, Shenzhen Campus of Sun Yat-sen University, Sun Yat-sen University, Shenzhen, 518107, China

    Tianyuan Xue, Zhirang Zhang, Tianliang Fang, Baoqi Li, Yuan Li, Liyan Li, Fangfang Duan, Fanqiang Meng & Xudong Zhang

  2. Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Key Laboratory of Stem Cell and Regenerative Tissue Engineering, School of Basic Medical Sciences, Guangdong Medical University, Dongguan, 523808, China

    Xin Liang

  3. The First People’s Hospital of Chenzhou, Chenzhou, 423000, China

    Yanghua Jiang

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Xue, T., Zhang, Z., Fang, T. et al. Cellular vesicles expressing PD-1-blocking scFv reinvigorate T cell immunity against cancer. Nano Res. 15, 5295–5304 (2022). https://doi.org/10.1007/s12274-022-4182-0

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