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Supplementary Figure legends from Metformin Reprograms Tryptophan Metabolism to Stimulate CD8+ T-cell Function in Colorectal Cancer

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posted on 2023-07-14, 08:21 authored by Xiaowen Huang, Tiantian Sun, Jilin Wang, Xialu Hong, Huimin Chen, Tingting Yan, Chengbei Zhou, Danfeng Sun, Chen Yang, TaChung Yu, Wenyu Su, Wan Du, Hua Xiong

This file contains the legends of supplementary figures.

Funding

National Natural Science Foundation of China (NSFC)

the Shanghai Municipal Education Commission-Gaoyuan and Gaofeng Clinical Medicine Grant

the Major health science and technology projects in ZheJiang Province

Shanghai Pujiang Program

Shanghai Rising-Star Program

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ARTICLE ABSTRACT

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.

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