Metformin Reprograms Tryptophan Metabolism to Stimulate CD8+ T-cell Function in Colorectal Cancer

• Published in: Cancer research (Chicago, Ill.) Ill.), 2023-07, Vol.83 (14), p.2358-2371
• Main Authors: Huang, Xiaowen, Sun, Tiantian, Wang, Jilin, Hong, Xialu, Chen, Huimin, Yan, Tingting, Zhou, Chengbei, Sun, Danfeng, Yang, Chen, Yu, TaChung, Su, Wenyu, Du, Wan, Xiong, Hua
• Format: Article
• Language: English
• Subjects: CD8-Positive T-Lymphocytes; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - metabolism; Humans; Immunosuppression Therapy; Metformin - pharmacology; Metformin - therapeutic use; Tryptophan; Tumor Microenvironment
• ISSN: 0008-5472; 1538-7445
• 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.