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Pancreatic tumor eradication via selective Pin1 inhibition in cancer-associated fibroblasts and T lymphocytes engagement

Author

Listed:
  • Jiaye Liu

    (Sichuan University
    Sichuan University
    Sichuan University and Collaborative Innovation Center
    Sichuan University)

  • Yang Wang

    (Karolinska Institute)

  • Chunyang Mu

    (Sichuan University)

  • Meng Li

    (Chinese Academy of Sciences
    Bioland Laboratory)

  • Kewei Li

    (Sichuan University)

  • Shan Li

    (Army Medical University)

  • Wenshuang Wu

    (Sichuan University
    Sichuan University)

  • Lingyao Du

    (Sichuan University)

  • Xiaoyun Zhang

    (Sichuan University)

  • Chuan Li

    (Sichuan University)

  • Wei Peng

    (Sichuan University)

  • Junyi Shen

    (Sichuan University)

  • Yang Liu

    (Sichuan University
    Sichuan University)

  • Dujiang Yang

    (Sichuan University)

  • Kaixiang Zhang

    (Sichuan University
    Sichuan University)

  • Qingyang Ning

    (Sichuan University
    Sichuan University)

  • Xiaoying Fu

    (Sichuan University)

  • Yu Zeng

    (Sichuan University)

  • Yinyun Ni

    (Sichuan University)

  • Zongguang Zhou

    (Sichuan University)

  • Yi Liu

    (Sichuan University)

  • Yiguo Hu

    (Sichuan University and Collaborative Innovation Center)

  • Xiaofeng Zheng

    (Sichuan University)

  • Tianfu Wen

    (Sichuan University)

  • Zhihui Li

    (Sichuan University
    Sichuan University)

  • Yong Liu

    (Sichuan University)

Abstract

Cancer associated fibroblasts (CAFs) support tumors via multiple mechanisms, including maintaining the immunosuppressive tumor microenvironment and limiting infiltration of immune cells. The prolyl isomerase Pin1, whose overexpression in CAFs has not been fully profiled yet, plays critical roles in tumor initiation and progression. To decipher effects of selective Pin1 inhibition in CAFs on pancreatic cancer, here we formulate a DNA-barcoded micellular system (DMS) encapsulating the Pin1 inhibitor AG17724. DMS functionalized with CAF-targeting anti-FAP-α antibodies (antiCAFs-DMS) can selectively inhibit Pin1 in CAFs, leading to efficacious but transient tumor growth inhibition. We further integrate DNA aptamers (AptT), which can engage CD8+ T lymphocytes, to obtain a bispecific antiCAFs-DMS-AptT system. AntiCAFs-DMS-AptT inhibits tumor growth in subcutaneous and orthotopic pancreatic cancer models.

Suggested Citation

  • Jiaye Liu & Yang Wang & Chunyang Mu & Meng Li & Kewei Li & Shan Li & Wenshuang Wu & Lingyao Du & Xiaoyun Zhang & Chuan Li & Wei Peng & Junyi Shen & Yang Liu & Dujiang Yang & Kaixiang Zhang & Qingyang , 2022. "Pancreatic tumor eradication via selective Pin1 inhibition in cancer-associated fibroblasts and T lymphocytes engagement," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-31928-7
    DOI: 10.1038/s41467-022-31928-7
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    as
    1. Elena Campaner & Alessandra Rustighi & Alessandro Zannini & Alberto Cristiani & Silvano Piazza & Yari Ciani & Ori Kalid & Gali Golan & Erkan Baloglu & Sharon Shacham & Barbara Valsasina & Ulisse Cucch, 2017. "A covalent PIN1 inhibitor selectively targets cancer cells by a dual mechanism of action," Nature Communications, Nature, vol. 8(1), pages 1-15, August.
    2. Zvi Yaari & Dana da Silva & Assaf Zinger & Evgeniya Goldman & Ashima Kajal & Rafi Tshuva & Efrat Barak & Nitsan Dahan & Dov Hershkovitz & Mor Goldfeder & Janna Shainsky Roitman & Avi Schroeder, 2016. "Theranostic barcoded nanoparticles for personalized cancer medicine," Nature Communications, Nature, vol. 7(1), pages 1-10, December.
    3. Ankur Chakravarthy & Lubaba Khan & Nathan Peter Bensler & Pinaki Bose & Daniel D. De Carvalho, 2018. "TGF-β-associated extracellular matrix genes link cancer-associated fibroblasts to immune evasion and immunotherapy failure," Nature Communications, Nature, vol. 9(1), pages 1-10, December.
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