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Reinvigoration of cytotoxic T lymphocytes in microsatellite instability-high colon adenocarcinoma through lysosomal degradation of PD-L1

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  • Dan Liu

    (The First Affiliated Hospital of Xi’an Jiaotong University
    The First Affiliated Hospital of Xi’an Jiaotong University)

  • Jin Yan

    (The Second Affiliated Hospital of Xi’an Jiaotong University
    The Second Affiliated Hospital of Xi’an Jiaotong University)

  • Fang Ma

    (The Second Affiliated Hospital of Xi’an Jiaotong University)

  • Jingmei Wang

    (The Second Affiliated Hospital of Xi’an Jiaotong University)

  • Siqi Yan

    (The Second Affiliated Hospital of Xi’an Jiaotong University)

  • Wangxiao He

    (The First Affiliated Hospital of Xi’an Jiaotong University
    The First Affiliated Hospital of Xi’an Jiaotong University
    The Second Affiliated Hospital of Xi’an Jiaotong University)

Abstract

Compensation and intracellular storage of PD-L1 may compromise the efficacy of antibody drugs targeting the conformational blockade of PD1/PD-L1 on the cell surface. Alternative therapies aiming to reduce the overall cellular abundance of PD-L1 thus might overcome resistance to conventional immune checkpoint blockade. Here we show by bioinformatics analysis that colon adenocarcinoma (COAD) with high microsatellite instability (MSI-H) presents the most promising potential for this therapeutic intervention, and that overall PD-L1 abundance could be controlled via HSC70-mediated lysosomal degradation. Proteomic and metabolomic analyses of mice COAD with MSI-H in situ unveil a prominent acidic tumor microenvironment. To harness these properties, an artificial protein, IgP β, is engineered using pH-responsive peptidic foldamers. This features customized peptide patterns and designed molecular function to facilitate interaction between neoplastic PD-L1 and HSC70. IgP β effectively reduces neoplastic PD-L1 levels via HSC70-mediated lysosomal degradation, thereby persistently revitalizing the action of tumor-infiltrating CD8 + T cells. Notably, the anti-tumor effect of lysosomal-degradation-based therapy surpasses that of antibody-based immune checkpoint blockade for MSI-H COAD in multiple mouse models. The presented strategy expands the use of peptidic foldamers in discovering artificial protein drugs for targeted cancer immunotherapy.

Suggested Citation

  • Dan Liu & Jin Yan & Fang Ma & Jingmei Wang & Siqi Yan & Wangxiao He, 2024. "Reinvigoration of cytotoxic T lymphocytes in microsatellite instability-high colon adenocarcinoma through lysosomal degradation of PD-L1," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-51386-7
    DOI: 10.1038/s41467-024-51386-7
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    References listed on IDEAS

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    1. Marian L. Burr & Christina E. Sparbier & Yih-Chih Chan & James C. Williamson & Katherine Woods & Paul A. Beavis & Enid Y. N. Lam & Melissa A. Henderson & Charles C. Bell & Sabine Stolzenburg & Omer Gi, 2017. "CMTM6 maintains the expression of PD-L1 and regulates anti-tumour immunity," Nature, Nature, vol. 549(7670), pages 101-105, September.
    2. Steven M. Banik & Kayvon Pedram & Simon Wisnovsky & Green Ahn & Nicholas M. Riley & Carolyn R. Bertozzi, 2020. "Lysosome-targeting chimaeras for degradation of extracellular proteins," Nature, Nature, vol. 584(7820), pages 291-297, August.
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