Department of Oncology, First Affiliated Hospital, Jinan University, Guangzhou, China.
Department of Geriatrics, The Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen, China.
Gut Microbes. 2023 Dec;15(2):2249143. doi: 10.1080/19490976.2023.2249143.
Recent studies have demonstrated that the antitumor immunity of immune cells can be modulated by gut microbiota and their metabolites. However, the underlying mechanisms remain unclear. Here, we showed that the serum butyric acid level is positively correlated with the expression of programmed cell death-1 (PD-1) on circulating CD8 and Vγ9 Vδ2 (Vδ2) T cells in patients with non-small cell lung cancer (NSCLC). Responder NSCLC patients exhibited higher levels of serum acetic acid, propionic acid, and butyric acid than non-responders. Depletion of the gut microbiota reduces butyrate levels in both feces and serum in tumor-bearing mice. Mechanistically, butyrate increased histone 3 lysine 27 acetylation (H3K27ac) at the promoter region of and in human CD8 T cells, thereby promoting the expression of PD-1/CD28 and enhancing the efficacy of anti-PD-1 therapy. Butyrate supplementation promotes the expression of antitumor cytokines in cytotoxic CD8 T cells by modulating the T-cell receptor (TCR) signaling pathway. Collectively, our findings reveal that the metabolite butyrate of the gut microbiota facilitates the efficacy of anti-PD-1 immunotherapy by modulating TCR signaling of cytotoxic CD8 T cells, and is a highly promising therapeutic biomarker for enhancing antitumor immunity.
最近的研究表明，免疫细胞的抗肿瘤免疫可以被肠道微生物群及其代谢物调节。然而，其潜在机制尚不清楚。在这里，我们表明，非小细胞肺癌（NSCLC）患者的循环 CD8 和 Vγ9Vδ2（Vδ2）T 细胞中程序性细胞死亡蛋白-1（PD-1）的表达与血清丁酸水平呈正相关。应答者 NSCLC 患者的血清乙酸、丙酸和丁酸水平高于无应答者。肠道微生物群的耗竭会降低荷瘤小鼠粪便和血清中的丁酸盐水平。在机制上，丁酸盐增加了人 CD8 T 细胞中 和 启动子区域的组蛋白 3 赖氨酸 27 乙酰化（H3K27ac），从而促进 PD-1/CD28 的表达，并增强抗 PD-1 治疗的疗效。丁酸盐通过调节 T 细胞受体（TCR）信号通路促进细胞毒性 CD8 T 细胞中抗肿瘤细胞因子的表达。总之，我们的研究结果表明，肠道微生物群的代谢物丁酸通过调节细胞毒性 CD8 T 细胞的 TCR 信号来促进抗 PD-1 免疫疗法的疗效，是增强抗肿瘤免疫的极具前景的治疗生物标志物。
