Enhanced bypass of PD-L1 translation reduces the therapeutic response to mTOR kinase inhibitors
Summary: 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 inhibit...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-07-01
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| Series: | Cell Reports |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124723007751 |
| _version_ | 1797787178918477824 |
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| author | Yanan Cao Qing Ye Murong Ma Qing-Bai She |
| author_facet | Yanan Cao Qing Ye Murong Ma Qing-Bai She |
| author_sort | Yanan Cao |
| collection | DOAJ |
| description | Summary: 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. |
| first_indexed | 2024-03-13T01:19:17Z |
| format | Article |
| id | doaj.art-36f825ef8de4434392da400190240cba |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-03-13T01:19:17Z |
| publishDate | 2023-07-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-36f825ef8de4434392da400190240cba2023-07-05T05:15:56ZengElsevierCell Reports2211-12472023-07-01427112764Enhanced bypass of PD-L1 translation reduces the therapeutic response to mTOR kinase inhibitorsYanan Cao0Qing Ye1Murong Ma2Qing-Bai She3Markey 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, USAMarkey 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, USAMarkey 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, USAMarkey 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; Corresponding authorSummary: 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.http://www.sciencedirect.com/science/article/pii/S2211124723007751CP: CancerCP: Molecular biology |
| spellingShingle | Yanan Cao Qing Ye Murong Ma Qing-Bai She Enhanced bypass of PD-L1 translation reduces the therapeutic response to mTOR kinase inhibitors Cell Reports CP: Cancer CP: Molecular biology |
| title | Enhanced bypass of PD-L1 translation reduces the therapeutic response to mTOR kinase inhibitors |
| title_full | Enhanced bypass of PD-L1 translation reduces the therapeutic response to mTOR kinase inhibitors |
| title_fullStr | Enhanced bypass of PD-L1 translation reduces the therapeutic response to mTOR kinase inhibitors |
| title_full_unstemmed | Enhanced bypass of PD-L1 translation reduces the therapeutic response to mTOR kinase inhibitors |
| title_short | Enhanced bypass of PD-L1 translation reduces the therapeutic response to mTOR kinase inhibitors |
| title_sort | enhanced bypass of pd l1 translation reduces the therapeutic response to mtor kinase inhibitors |
| topic | CP: Cancer CP: Molecular biology |
| url | http://www.sciencedirect.com/science/article/pii/S2211124723007751 |
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