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 considerat...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 theidentification of new biomarkers and immune checkpoints. Transmembrane 4 L six family member 5 (TM4SF5) is known to promoteHCC, but it remains unclear how cancerous hepatocytes avoid immune surveillance and whether avoidance can be blocked. Weinvestigated how TM4SF5-mediated hepatic tumorigenesis avoids surveillance by natural killer (NK) cells, which are prevalent in theliver, and whether the avoidance can be blocked by anti-TM4SF5 agents. We used comprehensive structure activity relationshipanalysis to identify TM4SF5-specific isoxazole (TSI)-based small molecules that inhibit TM4SF5-mediated effects. TM4SF5 expressedby hepatocytes reduced NK cell cytotoxicity by downregulating stimulatory ligands/receptors, including signaling lymphocyticactivation molecule family member 7 (SLAMF7). TM4SF5 bound SLAMF7 depending on N-glycosylation and caused intracellulartrafficking of SLAMF7 from the plasma membrane to lysosomes for degradation. TSI treatments in cell lines and animal models ofHCC blocked this binding, intracellular trafficking, and downregulation, resulting in higher levels of stimulatory NK cell ligands. Inmouse 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 NKcell surveillance. These findings suggest that TSIs can inhibit TM4SF5-mediated liver carcinogenesis by increasing NK cellsurveillance.展开更多
基金supported by the National Research Foundation of Korea(NRF)funded by the Korea government(MSIT)(NRF-2022R1C1C2003502)to HSKby Basic Science Research Program through the National Research Foundation of Korea(NRF)funded by the Ministry of Science,ICT&Future Planning(NRF-2020R1A2C3008993 and NRF-2021M3A9D3024752)to J.W.L.Graphical elements used in the figures of this manuscript were created with BioRender.com.
文摘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 theidentification of new biomarkers and immune checkpoints. Transmembrane 4 L six family member 5 (TM4SF5) is known to promoteHCC, but it remains unclear how cancerous hepatocytes avoid immune surveillance and whether avoidance can be blocked. Weinvestigated how TM4SF5-mediated hepatic tumorigenesis avoids surveillance by natural killer (NK) cells, which are prevalent in theliver, and whether the avoidance can be blocked by anti-TM4SF5 agents. We used comprehensive structure activity relationshipanalysis to identify TM4SF5-specific isoxazole (TSI)-based small molecules that inhibit TM4SF5-mediated effects. TM4SF5 expressedby hepatocytes reduced NK cell cytotoxicity by downregulating stimulatory ligands/receptors, including signaling lymphocyticactivation molecule family member 7 (SLAMF7). TM4SF5 bound SLAMF7 depending on N-glycosylation and caused intracellulartrafficking of SLAMF7 from the plasma membrane to lysosomes for degradation. TSI treatments in cell lines and animal models ofHCC blocked this binding, intracellular trafficking, and downregulation, resulting in higher levels of stimulatory NK cell ligands. Inmouse 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 NKcell surveillance. These findings suggest that TSIs can inhibit TM4SF5-mediated liver carcinogenesis by increasing NK cellsurveillance.
