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Combining p53 mRNA nanotherapy with immune checkpoint blockade reprograms the immune microenvironment for effective cancer therapy

Author

Listed:
  • Yuling Xiao

    (Brigham and Women’s Hospital, Harvard Medical School)

  • Jiang Chen

    (Massachusetts General Hospital and Harvard Medical School
    Zhejiang University)

  • Hui Zhou

    (Brigham and Women’s Hospital, Harvard Medical School
    Wuhan University School of Pharmaceutical Sciences)

  • Xiaodong Zeng

    (Brigham and Women’s Hospital, Harvard Medical School
    Wuhan University School of Pharmaceutical Sciences)

  • Zhiping Ruan

    (Massachusetts General Hospital and Harvard Medical School
    First Affiliated Hospital of Xi’an Jiaotong University)

  • Zhangya Pu

    (Massachusetts General Hospital and Harvard Medical School)

  • Xingya Jiang

    (Brigham and Women’s Hospital, Harvard Medical School)

  • Aya Matsui

    (Massachusetts General Hospital and Harvard Medical School)

  • Lingling Zhu

    (Massachusetts General Hospital and Harvard Medical School)

  • Zohreh Amoozgar

    (Massachusetts General Hospital and Harvard Medical School)

  • Dean Shuailin Chen

    (Brigham and Women’s Hospital, Harvard Medical School)

  • Xiangfei Han

    (Brigham and Women’s Hospital, Harvard Medical School)

  • Dan G. Duda

    (Massachusetts General Hospital and Harvard Medical School)

  • Jinjun Shi

    (Brigham and Women’s Hospital, Harvard Medical School)

Abstract

Immunotherapy with immune checkpoint blockade (ICB) has shown limited benefits in hepatocellular carcinoma (HCC) and other cancers, mediated in part by the immunosuppressive tumor microenvironment (TME). As p53 loss of function may play a role in immunosuppression, we herein examine the effects of restoring p53 expression on the immune TME and ICB efficacy. We develop and optimize a CXCR4-targeted mRNA nanoparticle platform to effectively induce p53 expression in HCC models. Using p53-null orthotopic and ectopic models of murine HCC, we find that combining CXCR4-targeted p53 mRNA nanoparticles with anti-PD-1 therapy effectively induces global reprogramming of cellular and molecular components of the immune TME. This effect results in improved anti-tumor effects compared to anti-PD-1 therapy or therapeutic p53 expression alone. Thus, our findings demonstrate the reversal of immunosuppression in HCC by a p53 mRNA nanomedicine when combined with ICB and support the implementation of this strategy for cancer treatment.

Suggested Citation

  • Yuling Xiao & Jiang Chen & Hui Zhou & Xiaodong Zeng & Zhiping Ruan & Zhangya Pu & Xingya Jiang & Aya Matsui & Lingling Zhu & Zohreh Amoozgar & Dean Shuailin Chen & Xiangfei Han & Dan G. Duda & Jinjun , 2022. "Combining p53 mRNA nanotherapy with immune checkpoint blockade reprograms the immune microenvironment for effective cancer therapy," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-28279-8
    DOI: 10.1038/s41467-022-28279-8
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    References listed on IDEAS

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    1. Wen Xue & Lars Zender & Cornelius Miething & Ross A. Dickins & Eva Hernando & Valery Krizhanovsky & Carlos Cordon-Cardo & Scott W. Lowe, 2007. "Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas," Nature, Nature, vol. 445(7128), pages 656-660, February.
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    1. Zhaoting Li & Fanyi Mo & Yixin Wang & Wen Li & Yu Chen & Jun Liu & Ting-Jing Chen-Mayfield & Quanyin Hu, 2022. "Enhancing Gasdermin-induced tumor pyroptosis through preventing ESCRT-dependent cell membrane repair augments antitumor immune response," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    2. Wenquan Ou & Samantha Stewart & Alisa White & Elyahb A. Kwizera & Jiangsheng Xu & Yuanzhang Fang & James G. Shamul & Changqing Xie & Suliat Nurudeen & Nikki P. Tirada & Xiongbin Lu & Katherine H. R. T, 2023. "In-situ cryo-immune engineering of tumor microenvironment with cold-responsive nanotechnology for cancer immunotherapy," Nature Communications, Nature, vol. 14(1), pages 1-20, December.

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