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

Dan Liu, Jin Yan (), Fang Ma, Jingmei Wang, Siqi Yan and Wangxiao He ()
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Dan Liu: The First Affiliated Hospital of Xi’an Jiaotong University
Jin Yan: 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

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-51386-7

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