Abstract
Increased PD-L1 expression in cancer cells is known to enhance immunosuppression, but the mechanism underlying PD-L1 upregulation is incompletely characterized. We show that PD-L1 expression is upregulated through internal ribosomal entry site (IRES)-mediated translation upon mTORC1 inhibition. We identify an IRES element in the PD-L1 5′-UTR that permits cap-independent translation and promotes continuous production of PD-L1 protein despite effective inhibition of mTORC1. eIF4A is found to be a key PD-L1 IRES-binding protein that enhances PD-L1 IRES activity and protein production in tumor cells treated with mTOR kinase inhibitors (mTORkis). Notably, treatment with mTORkis in vivo elevates PD-L1 levels and reduces the number of tumor-infiltrating lymphocytes in immunogenic tumors, but anti-PD-L1 immunotherapy restores antitumor immunity and enhances the therapeutic efficacy of mTORkis. These findings report a molecular mechanism for regulating PD-L1 expression through bypassing mTORC1-mediated cap-dependent translation and provide a rationale for targeting PD-L1 immune checkpoint to improve mTOR-targeted therapy.
Original language | English |
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Article number | 112764 |
Journal | Cell Reports |
Volume | 42 |
Issue number | 7 |
DOIs | |
State | Published - Jul 25 2023 |
Bibliographical note
Publisher Copyright:© 2023 The Author(s)
Keywords
- 4E-BP1
- CP: Cancer
- CP: Molecular biology
- IRES
- PD-L1
- eIF4A
- immunosuppression
- mTOR
ASJC Scopus subject areas
- General Biochemistry, Genetics and Molecular Biology