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Engineering tumor-specific gene nanomedicine to recruit and activate T cells for enhanced immunotherapy

Author

Listed:
  • Yue Wang

    (South China University of Technology, Guangzhou International Campus)

  • Shi-Kun Zhou

    (South China University of Technology, Guangzhou International Campus)

  • Yan Wang

    (South China University of Technology)

  • Zi-Dong Lu

    (South China University of Technology)

  • Yue Zhang

    (South China University of Technology, Guangzhou International Campus
    South China University of Technology)

  • Cong-Fei Xu

    (South China University of Technology, Guangzhou International Campus
    South China University of Technology
    South China University of Technology)

  • Jun Wang

    (South China University of Technology, Guangzhou International Campus
    South China University of Technology
    South China University of Technology)

Abstract

PD-1/PD-L1 blockade therapy that eliminates T-cell inhibition signals is successful, but poor benefits are often observed. Increasing T-cell infiltration and quantity of PD-1/PD-L1 inhibitors in tumor can improve efficacy but remains challenging. Here, we devise tumor-specific gene nanomedicines to mobilize tumor cells to secrete CXCL9 (T-cell chemokine) and anti-PD-L1 scFv (αPD-L1, PD-L1 blocking agent) for enhanced immunotherapy. The tyrosinase promoter-driven NPTyr-C9AP can specifically co-express CXCL9 and αPD-L1 in melanoma cells, thereby forming a CXCL9 gradient for T-cell recruitment and high intratumoral αPD-L1 concentration for enhancing T-cell activation. As a result, NPTyr-C9AP shows strong antimelanoma effects. Moreover, specific co-expression of CXCL9 and αPD-L1 in various tumor cells is achieved by replacing the tyrosinase promoter of NPTyr-C9AP with a survivin promoter, which increases T-cell infiltration and activation and therapeutic efficacy in multiple tumors in female mice. This study provides a strategy to maximize the immunotherapeutic outcome regardless of the heterogeneous tumor microenvironment.

Suggested Citation

  • Yue Wang & Shi-Kun Zhou & Yan Wang & Zi-Dong Lu & Yue Zhang & Cong-Fei Xu & Jun Wang, 2023. "Engineering tumor-specific gene nanomedicine to recruit and activate T cells for enhanced immunotherapy," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-37656-w
    DOI: 10.1038/s41467-023-37656-w
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    References listed on IDEAS

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    1. Cheng-Tao Jiang & Kai-Ge Chen & An Liu & Hua Huang & Ya-Nan Fan & Dong-Kun Zhao & Qian-Ni Ye & Hou-Bing Zhang & Cong-Fei Xu & Song Shen & Meng-Hua Xiong & Jin-Zhi Du & Xian-Zhu Yang & Jun Wang, 2021. "Immunomodulating nano-adaptors potentiate antibody-based cancer immunotherapy," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
    2. Chunbai He & Xiaopin Duan & Nining Guo & Christina Chan & Christopher Poon & Ralph R. Weichselbaum & Wenbin Lin, 2016. "Core-shell nanoscale coordination polymers combine chemotherapy and photodynamic therapy to potentiate checkpoint blockade cancer immunotherapy," Nature Communications, Nature, vol. 7(1), pages 1-12, November.
    3. Caroline Robert, 2020. "A decade of immune-checkpoint inhibitors in cancer therapy," Nature Communications, Nature, vol. 11(1), pages 1-3, December.
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