State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China.
Department of Breast Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China.
Nat Commun. 2021 May 11;12(1):2672. doi: 10.1038/s41467-021-22618-x.
Most patients with triple negative breast cancer (TNBC) do not respond to anti-PD1/PDL1 immunotherapy, indicating the necessity to explore immune checkpoint targets. B7H3 is a highly glycosylated protein. However, the mechanisms of B7H3 glycosylation regulation and whether the sugar moiety contributes to immunosuppression are unclear. Here, we identify aberrant B7H3 glycosylation and show that N-glycosylation of B7H3 at NXT motif sites is responsible for its protein stability and immunosuppression in TNBC tumors. The fucosyltransferase FUT8 catalyzes B7H3 core fucosylation at N-glycans to maintain its high expression. Knockdown of FUT8 rescues glycosylated B7H3-mediated immunosuppressive function in TNBC cells. Abnormal B7H3 glycosylation mediated by FUT8 overexpression can be physiologically important and clinically relevant in patients with TNBC. Notably, the combination of core fucosylation inhibitor 2F-Fuc and anti-PDL1 results in enhanced therapeutic efficacy in B7H3-positive TNBC tumors. These findings suggest that targeting the FUT8-B7H3 axis might be a promising strategy for improving anti-tumor immune responses in patients with TNBC.
大多数三阴性乳腺癌 (TNBC) 患者对抗 PD1/PDL1 免疫疗法没有反应，这表明有必要探索免疫检查点靶点。B7H3 是一种高度糖基化的蛋白。然而，B7H3 糖基化调控的机制以及糖基部分是否有助于免疫抑制尚不清楚。在这里，我们发现了异常的 B7H3 糖基化，并表明 B7H3 在 NXT 基序位点的 N-糖基化负责其在 TNBC 肿瘤中的蛋白稳定性和免疫抑制作用。岩藻糖基转移酶 FUT8 催化 B7H3 核心岩藻糖基化在 N-聚糖上，以维持其高表达。FUT8 的敲低可挽救 TNBC 细胞中糖基化 B7H3 介导的免疫抑制功能。由 FUT8 过表达介导的异常 B7H3 糖基化在 TNBC 患者中可能具有生理重要性和临床相关性。值得注意的是，核心岩藻糖基化抑制剂 2F-Fuc 与抗 PDL1 的联合使用可增强 B7H3 阳性 TNBC 肿瘤的治疗效果。这些发现表明，靶向 FUT8-B7H3 轴可能是提高 TNBC 患者抗肿瘤免疫反应的一种有前途的策略。
