Xue Qianqian, Peng Wenbei, Zhang Siyu, Wei Xiaoshan, Ye Linlin, Wang Zihao, Xiang Xuan, Liu Yao, Wang Haolei, Zhou Qiong
Department of Respiratory and Critical Care Medicine, Huazhong University of Science and Technology, Wuhan, China.
Department of Respiratory and Critical Care Medicine, Huazhong University of Science and Technology, Wuhan, China
J Immunother Cancer. 2024 Dec 25;12(12):e010040. doi: 10.1136/jitc-2024-010040.
Although tumor necrosis factor receptor 2 (TNFR2) has been recognized as an attractive next-generation candidate target for cancer immunotherapy, the factors that regulate the gene expression and their mechanistic effects on tumor-infiltrating regulatory T cells (Treg cells) remain poorly understood.
Single-cell RNA sequencing analysis was employed to analyze the phenotypic and functional differences between TNFR2 Treg cells and TNFR2 Treg cells. Malignant pleural effusion (MPE) from humans and mouse was used to investigate the potential mechanisms by which lactate regulates TNFR2 expression.
Treg cells with high TNFR2 expression exhibited elevated levels of immune checkpoint molecules. Additionally, the high expression of TNFR2 on Treg cells was positively correlated with a poor prognosis in MPE patients. Moreover, we revealed that lactate upregulated TNFR2 expression on Treg cells, thereby enhancing their immunosuppressive function in MPE. Mechanistically, lactate modulated the gene transcription of transcription factor nuclear factor-κB p65 (NF-κB p65) through histone H3K18 lactylation (H3K18la), subsequently upregulating the gene expression of TNFR2 and expediting the progression of MPE. Notably, lactate metabolism blockade combined with immune checkpoint blockade (ICB) therapy effectively enhanced the efficacy of ICB therapy, prolonged the survival time of MPE mice, and improved immunosuppression in the microenvironment of MPE.
The study explains the mechanism that regulates TNFR2 expression on Treg cells and its function in MPE progression, providing novel insights into the epigenetic regulation of tumor development and metabolic strategies for MPE treatment by targeting lactate metabolism in Treg cells.
尽管肿瘤坏死因子受体2（TNFR2）已被认为是癌症免疫治疗中颇具吸引力的下一代候选靶点，但调节该基因表达的因素及其对肿瘤浸润调节性T细胞（Treg细胞）的作用机制仍知之甚少。
采用单细胞RNA测序分析来剖析TNFR2 + Treg细胞与TNFR2 - Treg细胞之间的表型和功能差异。利用人类和小鼠的恶性胸腔积液（MPE）来探究乳酸调节TNFR2表达的潜在机制。
TNFR2表达高的Treg细胞表现出免疫检查点分子水平升高。此外，Treg细胞上TNFR2的高表达与MPE患者的不良预后呈正相关。而且，我们发现乳酸上调了Treg细胞上TNFR2的表达，从而增强了它们在MPE中的免疫抑制功能。机制上，乳酸通过组蛋白H3K18乳酸化（H3K18la）调节转录因子核因子-κB p65（NF-κB p65）的基因转录，随后上调TNFR2的基因表达并加速MPE的进展。值得注意的是，乳酸代谢阻断联合免疫检查点阻断（ICB）疗法有效地增强了ICB疗法的疗效，延长了MPE小鼠的生存时间，并改善了MPE微环境中的免疫抑制。
该研究解释了调节Treg细胞上TNFR2表达的机制及其在MPE进展中的作用，为肿瘤发展的表观遗传调控以及通过靶向Treg细胞中的乳酸代谢进行MPE治疗的代谢策略提供了新见解。
