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Signal Transduct. Target. Ther., Jan 20 2025, 10 (1) | https://doi.org/10.1038/s41392-024-02106-6
Isoxazole-based molecules restore NK cell immune surveillance in hepatocarcinogenesis by targeting TM4SF5 and SLAMF7 linkage
Ji Eon Kim1,2, Hyun Su Kim3, Wonsik Kim1, Eun Hae Lee1, Soyeon Kim1, Taewoo Kim3, Eun-Ae Shin1, Kyung-hee Pyo1, Haesong Lee1, Seo Hee Jin1, Jae-Ho Lee1, Soo-Min Byeon1, Dong Joo Kim1, Jinwook Jeong1, Jeongwon Lee1,2, Minjae Ohn1,2, Hyojung Lee1,2, Su Jong Yu4, Dongyun Shin5, Semi Kim6, Jun Yeob Yoo7, Seung-Chul Lee7, Young-Ger Suh3 and Jung Weon Lee1,2
1Department of Pharmacy, College of Pharmacy, Seoul National University, Seoul, Republic of Korea;
2Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, Republic of Korea;
3College of Pharmacy and Institute of Pharmaceutical Sciences, CHA University, Pocheon-si, Gyeonggi-do, Republic of Korea;
4Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea;
5College of Pharmacy, Gachon University, Incheon, Republic of Korea;
6Microbiome Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea and
7CHA Advanced Research Institute, Seongnam-si, Gyeonggi-do, Republic of Korea
Correspondence: Young-Ger Suh or Jung Weon Lee
These authors contributed equally: Ji Eon Kim, Hyun Su Kim, Wonsik Kim
1Department of Pharmacy, College of Pharmacy, Seoul National University, Seoul, Republic of Korea;
2Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, Republic of Korea;
3College of Pharmacy and Institute of Pharmaceutical Sciences, CHA University, Pocheon-si, Gyeonggi-do, Republic of Korea;
4Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea;
5College of Pharmacy, Gachon University, Incheon, Republic of Korea;
6Microbiome Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea and
7CHA Advanced Research Institute, Seongnam-si, Gyeonggi-do, Republic of Korea
Correspondence: Young-Ger Suh or Jung Weon Lee
These authors contributed equally: Ji Eon Kim, Hyun Su Kim, Wonsik Kim
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.
논문정보
- Research article
- 2025년 01월 (BRIC 등록일 2025-01-22)
- 국내 연구진
- 의약학 > 약학
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