Targeting EGFR-binding protein SLC7A11 enhancing antitumor immunity of T cells via inducing MHC-I antigen presentation in nasopharyngeal carcinoma
Abstract Approximately 80% of nasopharyngeal carcinoma (NPC) patients exhibit EGFR overexpression. The overexpression of EGFR has been linked to its potential role in modulating major histocompatibility complex class I (MHC-I) molecules. We discovered that EGFR, operating in a kinase-independent man...
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| Format: | Article |
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Nature Publishing Group
2025-01-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-024-07327-9 |
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| author | Haihua Wang Songqing Fan Yuting Zhan Yue Xu Yao Du Jiadi Luo Hongjing Zang Shuping Peng Weiyuan Wang |
| author_facet | Haihua Wang Songqing Fan Yuting Zhan Yue Xu Yao Du Jiadi Luo Hongjing Zang Shuping Peng Weiyuan Wang |
| author_sort | Haihua Wang |
| collection | DOAJ |
| description | Abstract Approximately 80% of nasopharyngeal carcinoma (NPC) patients exhibit EGFR overexpression. The overexpression of EGFR has been linked to its potential role in modulating major histocompatibility complex class I (MHC-I) molecules. We discovered that EGFR, operating in a kinase-independent manner, played a role in stabilizing the expression of SLC7A11, which subsequently inhibited MHC-I antigen presentation. This mechanism, in turn, provided protection to NPC cells against T cell-mediated cytotoxicity. The underlying molecular processes revealed that the high and stable expression of SLC7A11 hindered the nuclear entry of GR, thereby suppressing TAP1 transcription and the presentation of MHC-I molecules. Additionally, elevated SLC7A11 expression led to an increase in FAF2 expression and triggered ERAD-dependent degradation of MHC-I, resulting in a reduction of MHC-I molecules on the cell membrane. The NPC patients exhibiting high EGFR and low MHC-I expression, combined with a scarcity of CD8+ T cells (EGFRhighMHC-IlowCD8few phenotype), experienced considerably shorter overall survival times compared to other situations. What is more, our study demonstrated that sorafenib had the capability to enhance the MHC-I antigen presentation process, thereby facilitating T cell-mediated killing of NPC cells via targeting SLC7A11. Consequently, targeting SLC7A11 with sorafenib emerges as a promising therapeutic strategy for the treatment of NPC. |
| format | Article |
| id | doaj-art-825f7e661a31497cab2a73a93a19ea2c |
| institution | Kabale University |
| issn | 2041-4889 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Publishing Group |
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| series | Cell Death and Disease |
| spelling | doaj-art-825f7e661a31497cab2a73a93a19ea2c2025-01-19T12:40:47ZengNature Publishing GroupCell Death and Disease2041-48892025-01-0116112010.1038/s41419-024-07327-9Targeting EGFR-binding protein SLC7A11 enhancing antitumor immunity of T cells via inducing MHC-I antigen presentation in nasopharyngeal carcinomaHaihua Wang0Songqing Fan1Yuting Zhan2Yue Xu3Yao Du4Jiadi Luo5Hongjing Zang6Shuping Peng7Weiyuan Wang8Department of Pathology, The Second Xiangya Hospital, Central South UniversityDepartment of Pathology, The Second Xiangya Hospital, Central South UniversityDepartment of Pathology, The Second Xiangya Hospital, Central South UniversityDepartment of Pathology, The Second Xiangya Hospital, Central South UniversityDepartment of Pathology, The Second Xiangya Hospital, Central South UniversityDepartment of Pathology, The Second Xiangya Hospital, Central South UniversityDepartment of Pathology, The Second Xiangya Hospital, Central South UniversityCancer Research Institute, School of Basic Medical Science, Central South UniversityDepartment of Pathology, The Xiangya Hospital, Central South UniversityAbstract Approximately 80% of nasopharyngeal carcinoma (NPC) patients exhibit EGFR overexpression. The overexpression of EGFR has been linked to its potential role in modulating major histocompatibility complex class I (MHC-I) molecules. We discovered that EGFR, operating in a kinase-independent manner, played a role in stabilizing the expression of SLC7A11, which subsequently inhibited MHC-I antigen presentation. This mechanism, in turn, provided protection to NPC cells against T cell-mediated cytotoxicity. The underlying molecular processes revealed that the high and stable expression of SLC7A11 hindered the nuclear entry of GR, thereby suppressing TAP1 transcription and the presentation of MHC-I molecules. Additionally, elevated SLC7A11 expression led to an increase in FAF2 expression and triggered ERAD-dependent degradation of MHC-I, resulting in a reduction of MHC-I molecules on the cell membrane. The NPC patients exhibiting high EGFR and low MHC-I expression, combined with a scarcity of CD8+ T cells (EGFRhighMHC-IlowCD8few phenotype), experienced considerably shorter overall survival times compared to other situations. What is more, our study demonstrated that sorafenib had the capability to enhance the MHC-I antigen presentation process, thereby facilitating T cell-mediated killing of NPC cells via targeting SLC7A11. Consequently, targeting SLC7A11 with sorafenib emerges as a promising therapeutic strategy for the treatment of NPC.https://doi.org/10.1038/s41419-024-07327-9 |
| spellingShingle | Haihua Wang Songqing Fan Yuting Zhan Yue Xu Yao Du Jiadi Luo Hongjing Zang Shuping Peng Weiyuan Wang Targeting EGFR-binding protein SLC7A11 enhancing antitumor immunity of T cells via inducing MHC-I antigen presentation in nasopharyngeal carcinoma Cell Death and Disease |
| title | Targeting EGFR-binding protein SLC7A11 enhancing antitumor immunity of T cells via inducing MHC-I antigen presentation in nasopharyngeal carcinoma |
| title_full | Targeting EGFR-binding protein SLC7A11 enhancing antitumor immunity of T cells via inducing MHC-I antigen presentation in nasopharyngeal carcinoma |
| title_fullStr | Targeting EGFR-binding protein SLC7A11 enhancing antitumor immunity of T cells via inducing MHC-I antigen presentation in nasopharyngeal carcinoma |
| title_full_unstemmed | Targeting EGFR-binding protein SLC7A11 enhancing antitumor immunity of T cells via inducing MHC-I antigen presentation in nasopharyngeal carcinoma |
| title_short | Targeting EGFR-binding protein SLC7A11 enhancing antitumor immunity of T cells via inducing MHC-I antigen presentation in nasopharyngeal carcinoma |
| title_sort | targeting egfr binding protein slc7a11 enhancing antitumor immunity of t cells via inducing mhc i antigen presentation in nasopharyngeal carcinoma |
| url | https://doi.org/10.1038/s41419-024-07327-9 |
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