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

8 Scopus citations

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 languageEnglish
Article number112764
JournalCell Reports
Volume42
Issue number7
DOIs
StatePublished - 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

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