1. Academic Validation
  2. Enhanced bypass of PD-L1 translation reduces the therapeutic response to mTOR kinase inhibitors

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

  • Cell Rep. 2023 Jul 4;42(7):112764. doi: 10.1016/j.celrep.2023.112764.
Yanan Cao 1 Qing Ye 1 Murong Ma 1 Qing-Bai She 2
Affiliations

Affiliations

  • 1 Markey Cancer Center, University of Kentucky College of Medicine, Lexington, KY 40506, USA; Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, KY 40506, USA.
  • 2 Markey Cancer Center, University of Kentucky College of Medicine, Lexington, KY 40506, USA; Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, KY 40506, USA. Electronic address: qing-bai.she@uky.edu.
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.

Keywords

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

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