靶向 SLC7A5 的谷氨酰胺代谢重编程增强了抗-PD-1 对三阴性乳腺癌的疗效。
Targeting glutamine metabolic reprogramming of SLC7A5 enhances the efficacy of anti-PD-1 in triple-negative breast cancer.
发表日期：2023
作者：
Renhong Huang, Han Wang, Jin Hong, Jiayi Wu, Ou Huang, Jianrong He, Weiguo Chen, Yafen Li, Xiaosong Chen, Kunwei Shen, Zheng Wang
来源：
Cell Death & Disease
摘要：
三阴性乳腺癌（TNBC）是一种异质性疾病，其特点是代谢紊乱。代谢重编程和肿瘤细胞免疫逃逸在导致TNBC发生的肿瘤发生机制中起着不可或缺的作用。在本研究中，我们构建并验证了两个预后性谷氨酰胺代谢基因模型，A簇和B簇，以更好地区分TNBC患者的风险组。与风险A簇患者相比，簇B患者的生存结果更好，免疫细胞浸润更高。此外，我们建立了一个评分系统，谷氨酰胺代谢评分（GMS），用于评估谷氨酰胺代谢修饰的模式。我们发现溶质载体家族7成员5（SLC7A5），一种氨基酸转运蛋白，在TNBC细胞的谷氨酰胺代谢重编程中是最重要的基因之一，发挥着关键作用。抑制SLC7A5显著抑制了人类和小鼠TNBC细胞的增殖、迁移和侵袭。此外，SLC7A5的下调增加了CD8+T细胞的浸润。通过JPH203治疗介导的SLC7A5阻断与抗程序性细胞死亡1（PD-1）抗体联合，呈协同作用，增加了免疫细胞浸润率并抑制了肿瘤进展。因此，我们的研究结果突出了SLC7A5效应的分子机制，并增进了对以靶向谷氨酰胺代谢和免疫治疗为组合的新型TNBC疗法潜在益处的理解。版权所有 © 2023 Huang, Wang, Hong, Wu, Huang, He, Chen, Li, Chen, Shen and Wang.
Triple-negative breast cancer (TNBC) is a heterogeneous disease that is characterized by metabolic disruption. Metabolic reprogramming and tumor cell immune escape play indispensable roles in the tumorigenesis that leads to TNBC.In this study, we constructed and validated two prognostic glutamine metabolic gene models, Clusters A and B, to better discriminate between groups of TNBC patients based on risk. Compared with the risk Cluster A patients, the Cluster B patients tended to exhibit better survival outcomes and higher immune cell infiltration. In addition, we established a scoring system, the glutamine metabolism score (GMS), to assess the pattern of glutamine metabolic modification.We found that solute carrier family 7 member 5 (SLC7A5), an amino acid transporter, was the most important gene and plays a vital role in glutamine metabolism reprogramming in TNBC cells. Knocking down SLC7A5 significantly inhibited human and mouse TNBC cell proliferation, migration, and invasion. In addition, downregulation of SLC7A5 increased CD8+ T-cell infiltration. The combination of a SLC7A5 blockade mediated via JPH203 treatment and an anti-programmed cell death 1 (PD-1) antibody synergistically increased the immune cell infiltration rate and inhibited tumor progression.Hence, our results highlight the molecular mechanisms underlying SLC7A5 effects and lead to a better understanding of the potential benefit of targeting glutamine metabolism in combination with immunotherapy as a new therapy for TNBC.Copyright © 2023 Huang, Wang, Hong, Wu, Huang, He, Chen, Li, Chen, Shen and Wang.