PDF(Pubmed)
Abstract：
Immune checkpoint blockade therapy has drastically improved the prognosis of certain advanced-stage cancers. However, low response rates and immune-related adverse events remain important limitations. Here, we report that inhibiting ALG3, an a-1,3-mannosyltransferase involved in protein glycosylation in the endoplasmic reticulum (ER), can boost the response of tumors to immune checkpoint blockade therapy. Deleting N-linked glycosylation gene ALG3 in mouse cancer cells substantially attenuates their growth in mice in a manner depending on cytotoxic T cells. Furthermore, ALG3 inhibition or N-linked glycosylation inhibitor tunicamycin treatment synergizes with anti-PD1 therapy in suppressing tumor growth in mouse models of cancer. Mechanistically, we found that inhibiting ALG3 induced deficiencies of post-translational N-linked glycosylation modification and led to excessive lipid accumulation through sterol-regulated element-binding protein (SREBP1)-dependent lipogenesis in cancer cells. N-linked glycosylation deficiency-mediated lipid hyperperoxidation induced immunogenic ferroptosis of cancer cells and promoted a pro-inflammatory microenvironment, which boosted anti-tumor immune responses. In human subjects with cancer, elevated levels of ALG3 expression in tumor tissues are associated with poor patient survival. Taken together, we reveal an unappreciated role of ALG3 in regulating tumor immunogenicity and propose a potential therapeutic strategy for enhancing cancer immunotherapy.
摘要：
免疫检查点阻断治疗已大大改善某些晚期癌症的预后。然而,低应答率和免疫相关不良事件仍然是重要的局限性.这里,我们报道抑制ALG3，一种参与内质网（ER）蛋白糖基化的α-1,3-甘露糖基转移酶，可以增强肿瘤对免疫检查点阻断治疗的反应。在小鼠癌细胞中删除N-连接的糖基化基因ALG3以取决于细胞毒性T细胞的方式基本上减弱了它们在小鼠中的生长。此外，ALG3抑制或N-连接糖基化抑制剂衣霉素治疗与抗PD1治疗在抑制癌症小鼠模型中的肿瘤生长中协同作用。机械上,我们发现,抑制ALG3诱导翻译后N-连接糖基化修饰的缺陷,并通过固醇调节元件结合蛋白(SREBP1)依赖性脂肪生成在癌细胞中导致脂质过度积累.N-连接糖基化缺陷介导的脂质高过氧化诱导肿瘤细胞的免疫原性铁凋亡并促进促炎微环境,增强了抗肿瘤免疫反应。在患有癌症的人类受试者中，肿瘤组织中ALG3表达水平的升高与患者生存率低相关。一起来看,我们揭示了ALG3在调节肿瘤免疫原性方面的未被重视的作用,并提出了增强癌症免疫治疗的潜在治疗策略.
