肿瘤细胞治疗研究
英文原题：Palmitoylation of TIM-3 promotes immune exhaustion and restrains antitumor immunity.
这些发现表明，DHHC9 催化的 TIM-3 棕榈酰化可促进其稳定性，导致免疫耗竭和抗肿瘤免疫功能受损。
含T细胞免疫球蛋白和黏蛋白结构域蛋白3（TIM-3）是一种免疫检查点，在免疫耗竭中发挥关键作用。然而，调控TIM-3表面表达和周转的机制知之甚少。我们报告，人TIM-3可被棕榈酰基转移酶DHHC9在半胱氨酸296位点（Cys296）进行棕榈酰化。棕榈酰化可通过阻止TIM-3与E3泛素连接酶HRD1结合而稳定TIM-3，从而抑制其多聚泛素化和降解。敲低DHHC9可减轻CAR-T（CAR-T）细胞耗竭；一种TIM-3棕榈酰化肽类抑制剂可加快TIM-3降解，并增强CAR-T细胞和自然杀伤（NK）细胞介导的抗肿瘤免疫。在肝细胞癌中，CD8+ T细胞和NK细胞中的DHHC9表达与TIM-3表达相关；对于TIM-3高表达患者，DHHC9高表达与较短生存期相关。这些发现表明，DHHC9催化的TIM-3棕榈酰化可提高其稳定性，进而促进免疫耗竭并损害抗肿瘤免疫。
T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3) is an immune checkpoint that has critical roles in immune exhaustion. However, little is known about the mechanisms that regulate TIM-3 surface expression and turnover. Here, we report that human TIM-3 is palmitoylated by the palmitoyltransferase DHHC9 at residue cysteine 296 (Cys 296 ). Palmitoylation stabilized TIM-3 by preventing binding to E3 ubiquitin ligase HRD1, thereby suppressing its polyubiquitination and degradation. DHHC9 knockdown attenuated chimeric antigen receptor T (CAR-T) cell exhaustion, and a peptidic inhibitor of TIM-3 palmitoylation accelerated TIM-3 degradation and enhanced antitumor immunity mediated by CAR-T cells and natural killer (NK) cells. In hepatocellular carcinoma, DHHC9 expression correlated with TIM-3 expression in CD8 + T cells and NK cells, and high DHHC9 expression was associated with shorter survival in patients with high TIM-3. These findings demonstrate that palmitoylation of TIM-3 catalyzed by DHHC9 promotes its stability, resulting in immune exhaustion and impaired antitumor immunity.
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