Isoxazole-based molecules restore NK cell immune surveillance in hepatocarcinogenesis by targeting TM4SF5 and SLAMF7 linkage
Abstract Dynamic communication between hepatocytes and the environment is critical in hepatocellular carcinoma (HCC) development. Clinical immunotherapy against HCC is currently unsatisfactory and needs more systemic considerations, including the identification of new biomarkers and immune checkpoin...
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2025-01-01
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| Series: | Signal Transduction and Targeted Therapy |
| Online Access: | https://doi.org/10.1038/s41392-024-02106-6 |
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| author | Ji Eon Kim Hyun Su Kim Wonsik Kim Eun Hae Lee Soyeon Kim Taewoo Kim Eun-Ae Shin Kyung-hee Pyo Haesong Lee Seo Hee Jin Jae-Ho Lee Soo-Min Byeon Dong Joo Kim Jinwook Jeong Jeongwon Lee Minjae Ohn Hyojung Lee Su Jong Yu Dongyun Shin Semi Kim Jun Yeob Yoo Seung-Chul Lee Young-Ger Suh Jung Weon Lee |
| author_facet | Ji Eon Kim Hyun Su Kim Wonsik Kim Eun Hae Lee Soyeon Kim Taewoo Kim Eun-Ae Shin Kyung-hee Pyo Haesong Lee Seo Hee Jin Jae-Ho Lee Soo-Min Byeon Dong Joo Kim Jinwook Jeong Jeongwon Lee Minjae Ohn Hyojung Lee Su Jong Yu Dongyun Shin Semi Kim Jun Yeob Yoo Seung-Chul Lee Young-Ger Suh Jung Weon Lee |
| author_sort | Ji Eon Kim |
| collection | DOAJ |
| description | Abstract Dynamic communication between hepatocytes and the environment is critical in hepatocellular carcinoma (HCC) development. Clinical immunotherapy against HCC is currently unsatisfactory and needs more systemic considerations, including the identification of new biomarkers and immune checkpoints. Transmembrane 4 L six family member 5 (TM4SF5) is known to promote HCC, but it remains unclear how cancerous hepatocytes avoid immune surveillance and whether avoidance can be blocked. We investigated how TM4SF5-mediated hepatic tumorigenesis avoids surveillance by natural killer (NK) cells, which are prevalent in the liver, and whether the avoidance can be blocked by anti-TM4SF5 agents. We used comprehensive structure activity relationship analysis to identify TM4SF5-specific isoxazole (TSI)-based small molecules that inhibit TM4SF5-mediated effects. TM4SF5 expressed by hepatocytes reduced NK cell cytotoxicity by downregulating stimulatory ligands/receptors, including signaling lymphocytic activation molecule family member 7 (SLAMF7). TM4SF5 bound SLAMF7 depending on N-glycosylation and caused intracellular trafficking of SLAMF7 from the plasma membrane to lysosomes for degradation. TSI treatments in cell lines and animal models of HCC blocked this binding, intracellular trafficking, and downregulation, resulting in higher levels of stimulatory NK cell ligands. In mouse xenograft models, TSI treatment abrogated HCC development by increasing the abundance and dispersion of Slamf7-positive cells in liver tissues, recapitulating the phenotype of Tm4sf5-knockout mice and indicating TSI-mediated restoration of NK cell surveillance. These findings suggest that TSIs can inhibit TM4SF5-mediated liver carcinogenesis by increasing NK cell surveillance. |
| format | Article |
| id | doaj-art-addb895ff9814918984b6f498b379722 |
| institution | Kabale University |
| issn | 2059-3635 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Signal Transduction and Targeted Therapy |
| spelling | doaj-art-addb895ff9814918984b6f498b3797222025-01-26T12:54:30ZengNature Publishing GroupSignal Transduction and Targeted Therapy2059-36352025-01-0110111810.1038/s41392-024-02106-6Isoxazole-based molecules restore NK cell immune surveillance in hepatocarcinogenesis by targeting TM4SF5 and SLAMF7 linkageJi Eon Kim0Hyun Su Kim1Wonsik Kim2Eun Hae Lee3Soyeon Kim4Taewoo Kim5Eun-Ae Shin6Kyung-hee Pyo7Haesong Lee8Seo Hee Jin9Jae-Ho Lee10Soo-Min Byeon11Dong Joo Kim12Jinwook Jeong13Jeongwon Lee14Minjae Ohn15Hyojung Lee16Su Jong Yu17Dongyun Shin18Semi Kim19Jun Yeob Yoo20Seung-Chul Lee21Young-Ger Suh22Jung Weon Lee23Department of Pharmacy, College of Pharmacy, Seoul National UniversityCollege of Pharmacy and Institute of Pharmaceutical Sciences, CHA UniversityDepartment of Pharmacy, College of Pharmacy, Seoul National UniversityDepartment of Pharmacy, College of Pharmacy, Seoul National UniversityDepartment of Pharmacy, College of Pharmacy, Seoul National UniversityCollege of Pharmacy and Institute of Pharmaceutical Sciences, CHA UniversityDepartment of Pharmacy, College of Pharmacy, Seoul National UniversityDepartment of Pharmacy, College of Pharmacy, Seoul National UniversityDepartment of Pharmacy, College of Pharmacy, Seoul National UniversityDepartment of Pharmacy, College of Pharmacy, Seoul National UniversityDepartment of Pharmacy, College of Pharmacy, Seoul National UniversityDepartment of Pharmacy, College of Pharmacy, Seoul National UniversityDepartment of Pharmacy, College of Pharmacy, Seoul National UniversityDepartment of Pharmacy, College of Pharmacy, Seoul National UniversityDepartment of Pharmacy, College of Pharmacy, Seoul National UniversityDepartment of Pharmacy, College of Pharmacy, Seoul National UniversityDepartment of Pharmacy, College of Pharmacy, Seoul National UniversityDepartment of Internal Medicine and Liver Research Institute, Seoul National University College of MedicineCollege of Pharmacy, Gachon UniversityMicrobiome Convergence Research Center, Korea Research Institute of Bioscience and BiotechnologyCHA Advanced Research InstituteCHA Advanced Research InstituteCollege of Pharmacy and Institute of Pharmaceutical Sciences, CHA UniversityDepartment of Pharmacy, College of Pharmacy, Seoul National UniversityAbstract Dynamic communication between hepatocytes and the environment is critical in hepatocellular carcinoma (HCC) development. Clinical immunotherapy against HCC is currently unsatisfactory and needs more systemic considerations, including the identification of new biomarkers and immune checkpoints. Transmembrane 4 L six family member 5 (TM4SF5) is known to promote HCC, but it remains unclear how cancerous hepatocytes avoid immune surveillance and whether avoidance can be blocked. We investigated how TM4SF5-mediated hepatic tumorigenesis avoids surveillance by natural killer (NK) cells, which are prevalent in the liver, and whether the avoidance can be blocked by anti-TM4SF5 agents. We used comprehensive structure activity relationship analysis to identify TM4SF5-specific isoxazole (TSI)-based small molecules that inhibit TM4SF5-mediated effects. TM4SF5 expressed by hepatocytes reduced NK cell cytotoxicity by downregulating stimulatory ligands/receptors, including signaling lymphocytic activation molecule family member 7 (SLAMF7). TM4SF5 bound SLAMF7 depending on N-glycosylation and caused intracellular trafficking of SLAMF7 from the plasma membrane to lysosomes for degradation. TSI treatments in cell lines and animal models of HCC blocked this binding, intracellular trafficking, and downregulation, resulting in higher levels of stimulatory NK cell ligands. In mouse xenograft models, TSI treatment abrogated HCC development by increasing the abundance and dispersion of Slamf7-positive cells in liver tissues, recapitulating the phenotype of Tm4sf5-knockout mice and indicating TSI-mediated restoration of NK cell surveillance. These findings suggest that TSIs can inhibit TM4SF5-mediated liver carcinogenesis by increasing NK cell surveillance.https://doi.org/10.1038/s41392-024-02106-6 |
| spellingShingle | Ji Eon Kim Hyun Su Kim Wonsik Kim Eun Hae Lee Soyeon Kim Taewoo Kim Eun-Ae Shin Kyung-hee Pyo Haesong Lee Seo Hee Jin Jae-Ho Lee Soo-Min Byeon Dong Joo Kim Jinwook Jeong Jeongwon Lee Minjae Ohn Hyojung Lee Su Jong Yu Dongyun Shin Semi Kim Jun Yeob Yoo Seung-Chul Lee Young-Ger Suh Jung Weon Lee Isoxazole-based molecules restore NK cell immune surveillance in hepatocarcinogenesis by targeting TM4SF5 and SLAMF7 linkage Signal Transduction and Targeted Therapy |
| title | Isoxazole-based molecules restore NK cell immune surveillance in hepatocarcinogenesis by targeting TM4SF5 and SLAMF7 linkage |
| title_full | Isoxazole-based molecules restore NK cell immune surveillance in hepatocarcinogenesis by targeting TM4SF5 and SLAMF7 linkage |
| title_fullStr | Isoxazole-based molecules restore NK cell immune surveillance in hepatocarcinogenesis by targeting TM4SF5 and SLAMF7 linkage |
| title_full_unstemmed | Isoxazole-based molecules restore NK cell immune surveillance in hepatocarcinogenesis by targeting TM4SF5 and SLAMF7 linkage |
| title_short | Isoxazole-based molecules restore NK cell immune surveillance in hepatocarcinogenesis by targeting TM4SF5 and SLAMF7 linkage |
| title_sort | isoxazole based molecules restore nk cell immune surveillance in hepatocarcinogenesis by targeting tm4sf5 and slamf7 linkage |
| url | https://doi.org/10.1038/s41392-024-02106-6 |
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