The Regulatory Axis of PD-L1 Isoform 2/TNF/T Cell Proliferation Is Required for the Canonical Immune-Suppressive Effects of PD-L1 Isoform 1 in Liver Cancer
Despite the well-studied effects of the full-length membrane-locating isoform Iso1 of Programmed Cell Death Protein-Ligand 1 (PD-L1) on immunosuppression, little is known about another membrane-locating isoform, Iso2. While expressional and survival analysis of liver cancer patients indicated that I...
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MDPI AG
2023-03-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/7/6314 |
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| author | Xixi Zheng Xingdong Chen Weicheng Wu |
| author_facet | Xixi Zheng Xingdong Chen Weicheng Wu |
| author_sort | Xixi Zheng |
| collection | DOAJ |
| description | Despite the well-studied effects of the full-length membrane-locating isoform Iso1 of Programmed Cell Death Protein-Ligand 1 (PD-L1) on immunosuppression, little is known about another membrane-locating isoform, Iso2. While expressional and survival analysis of liver cancer patients indicated that Iso2 plays a tumor-suppressive role, our results also indicated that the tumor-promoting and immune-suppressive effects of Iso1 depended on the positive expression of Iso2. Through mediation analysis, we discovered several downstream genes or pathways of Iso2 and investigated their effects on the Iso1-regulating survival. Among all potential downstream immune factors, Iso2 was inclined to activate the proliferation of T cells by regulating chemokine activity and increasing CD3 levels by promoting TNF expression. Similar results were confirmed in the Mongolian liver cancer cohort, and the Iso2/TNF/T-cell axis was verified in several other cancers in the TCGA cohort. Finally, we demonstrated the promoting effects of Iso2 in terms of producing TNF and increasing T cells both in vitro and in vivo. Our findings illustrate that PD-L1 Iso2 can increase the number of T cells in the tumor microenvironment by elevating TNF levels, which is a necessary part of the tumor-suppressive effects of Iso1 in liver cancer. |
| first_indexed | 2024-03-11T05:35:52Z |
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| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-11T05:35:52Z |
| publishDate | 2023-03-01 |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-738eb1c00ef140aca43f98442a8403ee2023-11-17T16:49:23ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-03-01247631410.3390/ijms24076314The Regulatory Axis of PD-L1 Isoform 2/TNF/T Cell Proliferation Is Required for the Canonical Immune-Suppressive Effects of PD-L1 Isoform 1 in Liver CancerXixi Zheng0Xingdong Chen1Weicheng Wu2State Key Laboratory of Genetic Engineering, Human Phenome Institute, School of Life Sciences, Fudan University, Shanghai 200438, ChinaState Key Laboratory of Genetic Engineering, Human Phenome Institute, School of Life Sciences, Fudan University, Shanghai 200438, ChinaState Key Laboratory of Genetic Engineering, Human Phenome Institute, School of Life Sciences, Fudan University, Shanghai 200438, ChinaDespite the well-studied effects of the full-length membrane-locating isoform Iso1 of Programmed Cell Death Protein-Ligand 1 (PD-L1) on immunosuppression, little is known about another membrane-locating isoform, Iso2. While expressional and survival analysis of liver cancer patients indicated that Iso2 plays a tumor-suppressive role, our results also indicated that the tumor-promoting and immune-suppressive effects of Iso1 depended on the positive expression of Iso2. Through mediation analysis, we discovered several downstream genes or pathways of Iso2 and investigated their effects on the Iso1-regulating survival. Among all potential downstream immune factors, Iso2 was inclined to activate the proliferation of T cells by regulating chemokine activity and increasing CD3 levels by promoting TNF expression. Similar results were confirmed in the Mongolian liver cancer cohort, and the Iso2/TNF/T-cell axis was verified in several other cancers in the TCGA cohort. Finally, we demonstrated the promoting effects of Iso2 in terms of producing TNF and increasing T cells both in vitro and in vivo. Our findings illustrate that PD-L1 Iso2 can increase the number of T cells in the tumor microenvironment by elevating TNF levels, which is a necessary part of the tumor-suppressive effects of Iso1 in liver cancer.https://www.mdpi.com/1422-0067/24/7/6314liver cancerprogrammed cell death protein-ligand 1immunology suppressionisoforms |
| spellingShingle | Xixi Zheng Xingdong Chen Weicheng Wu The Regulatory Axis of PD-L1 Isoform 2/TNF/T Cell Proliferation Is Required for the Canonical Immune-Suppressive Effects of PD-L1 Isoform 1 in Liver Cancer International Journal of Molecular Sciences liver cancer programmed cell death protein-ligand 1 immunology suppression isoforms |
| title | The Regulatory Axis of PD-L1 Isoform 2/TNF/T Cell Proliferation Is Required for the Canonical Immune-Suppressive Effects of PD-L1 Isoform 1 in Liver Cancer |
| title_full | The Regulatory Axis of PD-L1 Isoform 2/TNF/T Cell Proliferation Is Required for the Canonical Immune-Suppressive Effects of PD-L1 Isoform 1 in Liver Cancer |
| title_fullStr | The Regulatory Axis of PD-L1 Isoform 2/TNF/T Cell Proliferation Is Required for the Canonical Immune-Suppressive Effects of PD-L1 Isoform 1 in Liver Cancer |
| title_full_unstemmed | The Regulatory Axis of PD-L1 Isoform 2/TNF/T Cell Proliferation Is Required for the Canonical Immune-Suppressive Effects of PD-L1 Isoform 1 in Liver Cancer |
| title_short | The Regulatory Axis of PD-L1 Isoform 2/TNF/T Cell Proliferation Is Required for the Canonical Immune-Suppressive Effects of PD-L1 Isoform 1 in Liver Cancer |
| title_sort | regulatory axis of pd l1 isoform 2 tnf t cell proliferation is required for the canonical immune suppressive effects of pd l1 isoform 1 in liver cancer |
| topic | liver cancer programmed cell death protein-ligand 1 immunology suppression isoforms |
| url | https://www.mdpi.com/1422-0067/24/7/6314 |
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