Key Laboratory for Experimental Teratology of Ministry of Education and Department of Immunology, School of Basic Medical Sciences, Qilu Hospital, Cheeloo Medical College, Shandong University, 250012 Jinan, Shandong, China.
Department of Hepatology, Qilu Hospital, Cheeloo Medical College, Shandong University, 250012 Jinan, Shandong, China.
Sci Immunol. 2024 Nov 15;9(101):eadp7302. doi: 10.1126/sciimmunol.adp7302.
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). 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.
T 细胞免疫球蛋白和粘蛋白结构域蛋白 3（TIM-3）是一种免疫检查点，在免疫衰竭中具有关键作用。然而，关于调节 TIM-3 表面表达和周转的机制知之甚少。在这里，我们报告人类 TIM-3 被棕榈酰转移酶 DHHC9 在半胱氨酸残基 296（Cys）处棕榈酰化。棕榈酰化通过防止与 E3 泛素连接酶 HRD1 结合来稳定 TIM-3，从而抑制其多泛素化和降解。DHHC9 敲低减弱了嵌合抗原受体 T（CAR-T）细胞衰竭，TIM-3 棕榈酰化的肽抑制剂加速了 TIM-3 降解，并增强了由 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，DHHC9 在 CD8 T 细胞和 NK 细胞中的表达与 TIM-3 的表达相关，高 DHHC9 表达与高 TIM-3 患者的生存时间较短相关。这些发现表明，DHHC9 催化的 TIM-3 棕榈酰化促进其稳定性，导致免疫衰竭和抗肿瘤免疫受损。
