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 50-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.
Document Type
Article
Publication Date
7-2023
Digital Object Identifier (DOI)
https://doi.org/10.1016/j.celrep.2023.112764
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 P20 GM121327). 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).
Repository Citation
Cao, Yanan; Ye, Qing; Ma, Murong; and She, Qing-Bai, "Enhanced bypass of PD-L1 translation reduces the therapeutic response to mTOR kinase inhibitors" (2023). Markey Cancer Center Faculty Publications. 331.
https://uknowledge.uky.edu/markey_facpub/331
Notes/Citation Information
© 2023 The Author(s). This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).