PD-L1 Exon 3 Is a Hidden Switch of Its Expression and Function in Oral Cancer Cells
The interaction between programmed cell death 1 ligand 1 (PD-L1) and programmed cell death protein 1 (PD-1) protects tumor cells from immune surveillance. PD-L1 exon 3 is a potential alternative exon and encodes an Ig variable (IgV) domain. Here, we found that a lack of exon 3 leads to the significa...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-05-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/9/8193 |
| _version_ | 1797602443482103808 |
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| author | Lingyan Yan Yanan Sun Jihua Guo Rong Jia |
| author_facet | Lingyan Yan Yanan Sun Jihua Guo Rong Jia |
| author_sort | Lingyan Yan |
| collection | DOAJ |
| description | The interaction between programmed cell death 1 ligand 1 (PD-L1) and programmed cell death protein 1 (PD-1) protects tumor cells from immune surveillance. PD-L1 exon 3 is a potential alternative exon and encodes an Ig variable (IgV) domain. Here, we found that a lack of exon 3 leads to the significant loss of cellular membrane locations and the dramatically reduced protein expression of PD-L1, indicating that PD-L1 exon 3 is essential for its protein expression and translocation to the cell membrane. Notably, oral cancer cells show almost no exon 3 skipping to ensure the expression of the full-length, functional PD-L1 protein. We discovered two key exonic splicing enhancers (ESEs) for exon 3 inclusion. Two efficient antisense oligonucleotides (ASOs) were identified to block these two ESEs, which can significantly trigger exon 3 skipping and decrease the production of full-length, functional PD-L1 on the surface of cancer cells. Treatment of oral cancer cells with these ASOs significantly enhanced immune cells’ suppression of cancer cell proliferation. Surprisingly, these two ASOs also significantly inhibited cell growth and induced cell pyroptosis in oral cancer cells. Altogether, the results of our study demonstrate the pivotal roles of exon 3 in PD-L1 expression and provide a novel anti-PD-L1 method. |
| first_indexed | 2024-03-11T04:16:08Z |
| format | Article |
| id | doaj.art-5fe4a38849f34d0d945df9d1d0670f43 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-11T04:16:08Z |
| publishDate | 2023-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-5fe4a38849f34d0d945df9d1d0670f432023-11-17T23:06:14ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-05-01249819310.3390/ijms24098193PD-L1 Exon 3 Is a Hidden Switch of Its Expression and Function in Oral Cancer CellsLingyan Yan0Yanan Sun1Jihua Guo2Rong Jia3The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, Wuhan 430079, ChinaThe State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, Wuhan 430079, ChinaThe State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, Wuhan 430079, ChinaThe State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, Wuhan 430079, ChinaThe interaction between programmed cell death 1 ligand 1 (PD-L1) and programmed cell death protein 1 (PD-1) protects tumor cells from immune surveillance. PD-L1 exon 3 is a potential alternative exon and encodes an Ig variable (IgV) domain. Here, we found that a lack of exon 3 leads to the significant loss of cellular membrane locations and the dramatically reduced protein expression of PD-L1, indicating that PD-L1 exon 3 is essential for its protein expression and translocation to the cell membrane. Notably, oral cancer cells show almost no exon 3 skipping to ensure the expression of the full-length, functional PD-L1 protein. We discovered two key exonic splicing enhancers (ESEs) for exon 3 inclusion. Two efficient antisense oligonucleotides (ASOs) were identified to block these two ESEs, which can significantly trigger exon 3 skipping and decrease the production of full-length, functional PD-L1 on the surface of cancer cells. Treatment of oral cancer cells with these ASOs significantly enhanced immune cells’ suppression of cancer cell proliferation. Surprisingly, these two ASOs also significantly inhibited cell growth and induced cell pyroptosis in oral cancer cells. Altogether, the results of our study demonstrate the pivotal roles of exon 3 in PD-L1 expression and provide a novel anti-PD-L1 method.https://www.mdpi.com/1422-0067/24/9/8193programmed cell death 1 ligand 1exon skippingantisense oligonucleotideimmunotherapy |
| spellingShingle | Lingyan Yan Yanan Sun Jihua Guo Rong Jia PD-L1 Exon 3 Is a Hidden Switch of Its Expression and Function in Oral Cancer Cells International Journal of Molecular Sciences programmed cell death 1 ligand 1 exon skipping antisense oligonucleotide immunotherapy |
| title | PD-L1 Exon 3 Is a Hidden Switch of Its Expression and Function in Oral Cancer Cells |
| title_full | PD-L1 Exon 3 Is a Hidden Switch of Its Expression and Function in Oral Cancer Cells |
| title_fullStr | PD-L1 Exon 3 Is a Hidden Switch of Its Expression and Function in Oral Cancer Cells |
| title_full_unstemmed | PD-L1 Exon 3 Is a Hidden Switch of Its Expression and Function in Oral Cancer Cells |
| title_short | PD-L1 Exon 3 Is a Hidden Switch of Its Expression and Function in Oral Cancer Cells |
| title_sort | pd l1 exon 3 is a hidden switch of its expression and function in oral cancer cells |
| topic | programmed cell death 1 ligand 1 exon skipping antisense oligonucleotide immunotherapy |
| url | https://www.mdpi.com/1422-0067/24/9/8193 |
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