Metformin Reprograms Tryptophan Metabolism to Stimulate CD8+ T-cell Function in Colorectal Cancer.
Cancer Res
; 83(14): 2358-2371, 2023 07 14.
Article
en En
| MEDLINE
| ID: mdl-37195082
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. SIGNIFICANCE:
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.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Neoplasias Colorrectales
/
Metformina
Límite:
Humans
Idioma:
En
Revista:
Cancer Res
Año:
2023
Tipo del documento:
Article
País de afiliación:
China