Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University; Shanghai Institute of Digestive Disease, Shanghai, China.
State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Cancer Res. 2023 Jul 14;83(14):2358-2371. doi: 10.1158/0008-5472.CAN-22-3042.
Colorectal carcinogenesis coincides with immune cell dysfunction. Metformin has been reported to play a role in stimulating antitumor immunity, suggesting it could be used to overcome immunosuppression in colorectal cancer. Herein, using single-cell RNA sequencing (scRNA-seq), we showed that metformin remodels the immune landscape of colorectal cancer. In particular, metformin treatment expanded the proportion of CD8+ T cells and potentiated their function. Analysis of the metabolic activities of cells in the colorectal cancer tumor microenvironment (TME) at a single-cell resolution demonstrated that metformin reprogrammed tryptophan metabolism, which was reduced in colorectal cancer cells and increased in CD8+ T cells. Untreated colorectal cancer cells outcompeted CD8+ T cells for tryptophan, leading to impaired CD8+ T-cell function. Metformin in turn reduced tryptophan uptake by colorectal cancer cells, thereby restoring tryptophan availability for CD8+ T cells and increasing their cytotoxicity. Metformin inhibited tryptophan uptake in colorectal cancer cells by downregulating MYC, which led to a reduction in the tryptophan transporter SLC7A5. This work highlights metformin as an essential regulator of T-cell antitumor immunity by reprogramming tryptophan metabolism, suggesting it could be a potential immunotherapeutic strategy for treating colorectal cancer.
Analysis of the impact of metformin on the colorectal cancer immunometabolic landscape at a single-cell resolution shows that metformin alters cancer cell tryptophan metabolism to stimulate CD8+ T-cell antitumor activity.
结直肠癌的发生与免疫细胞功能障碍同时发生。据报道，二甲双胍在刺激抗肿瘤免疫方面发挥作用，这表明它可以用于克服结直肠癌的免疫抑制。在此，我们使用单细胞 RNA 测序（scRNA-seq）表明，二甲双胍重塑了结直肠癌的免疫景观。特别是，二甲双胍治疗扩大了 CD8+T 细胞的比例并增强了其功能。在单细胞分辨率下分析结直肠癌肿瘤微环境（TME）中细胞的代谢活性表明，二甲双胍重新编程了色氨酸代谢，结直肠癌细胞中的色氨酸减少，CD8+T 细胞中的色氨酸增加。未经处理的结直肠癌细胞会与 CD8+T 细胞竞争色氨酸，从而导致 CD8+T 细胞功能受损。二甲双胍反过来通过降低结直肠癌细胞对色氨酸的摄取，从而恢复 CD8+T 细胞的色氨酸可用性并增加其细胞毒性。二甲双胍通过下调 MYC 抑制结直肠癌细胞摄取色氨酸，从而减少色氨酸转运蛋白 SLC7A5。这项工作强调了二甲双胍通过重新编程色氨酸代谢作为 T 细胞抗肿瘤免疫的重要调节剂的作用，表明它可能是治疗结直肠癌的一种潜在免疫治疗策略。
单细胞分辨率分析二甲双胍对结直肠癌免疫代谢景观的影响表明，二甲双胍改变了癌细胞的色氨酸代谢，以刺激 CD8+T 细胞的抗肿瘤活性。
