Enhanced bypass of PD-L1 translation reduces the therapeutic response to mTOR kinase inhibitors

Yanan Cao, Qing Ye, Murong Ma, Qing Bai She

Research output: Contribution to journalArticlepeer-review


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 languageEnglish
Article number112764
JournalCell Reports
Issue number7
StatePublished - Jul 25 2023

Bibliographical note

Funding Information:
We thank the Markey Cancer Center’s Research Communication Office for assistance with manuscript preparation. This work was supported, in part, by NIH grants R01CA175105 (Q.-B.S.), R01CA203257 (Q.-B.S.), R21ES031712 (Q.-B.S.), T32CA165990 (M.M.), and the pilot grant (Q.-B.S.) from the University of Kentucky Center for Cancer and Metabolism (NIH P20M121327 ). This work was also supported in part by the Flow Cytometry and Immune Monitoring Shared Resource Facility of the University of Kentucky Markey Cancer Center ( NIH P30CA177558 ).

Publisher Copyright:
© 2023 The Author(s)


  • 4E-BP1
  • CP: Cancer
  • CP: Molecular biology
  • IRES
  • PD-L1
  • eIF4A
  • immunosuppression
  • mTOR

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology (all)


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