Glutamine deficiency promotes tumor growth by inducing ferroptosis in CD8+ T cells
10.13431/j.cnki.immunol.j.20230108
- VernacularTitle:谷氨酰胺缺乏诱导CD8+T细胞铁死亡促进肿瘤生长
- Author:
Long ZHANG
1
,
2
;
Luo LI
;
Meiying SHEN
;
Xiaojian HAN
;
Min YAN
;
Siyin CHEN
;
Aishun JIN
Author Information
1. 400016,重庆医科大学基础医学院免疫学教研室
2. 400016,肿瘤免疫基础与转化研究重庆市重点实验室
- Keywords:
Glutamine;
CD8+ T cells;
Ferroptosis
- From:
Immunological Journal
2023;39(10):829-838
- CountryChina
- Language:Chinese
-
Abstract:
This study was performed to explore the impact of glutamine(Gln)on the anti-tumor immune response of CD8+ T cells and its mechanism.TCGA database was used to analysis the relationship between tumor Gln metabolism and the quantity and functionality of infiltrating CD8+ T cells.CRISPR/Cas9 was employed to knock down GLS expression in mouse MC38 cells,and a mouse tumor model was established.Flow cytometry was conducted to assess tumor proliferation,apoptosis,and the quantity and functionality of tumor-infiltrating immune cells.Lymphocytes isolated from health individuals were treated with Gln-deficient media,complete media or media supplemented with GSH,RSL3 in vitro.Then the apoptosis,the expression levels of GPX4,Lipid-ROS,and effector function protein of CD8+ T cells were detected by flow cytometry.Furthermore,RNA-seq was performed to analyze the differential gene expression on the Gln-depleted CD8+ T cells.Data showed that tumor Gln metabolism was inversely associated with the quantity and functionality of tumor-infiltrating CD8+ T cells.Low expression of GLS in MC38 cells could inhibit C57BL/6 tumor growth,decrease Ki-67 expression,promote casepase-3 expression,increase the amount of tumor-infiltrating immune cells,suppress PD-1,TIM-3,and LAG-3 expression,and enhance CD137,CD107a,IFN-γ and TNF-α expression in tumor-infiltrating CD8+ T cells.RNA-seq results indicated an upregulation of ferroptosis genes TFRC,HMOX1,CYBB and SLC7A11 in CD8+ T cells following glutamine deficiency.Gln deficiency led to lower CD137,CD107a,IFN-γ,GSH,GPX4 expression,increased Lipid-ROS level,and caused cell death in CD8+ T cells.Supplementation of GSH upregulated GPX4 expression,downregulated Lipid-ROS level,and increased IFN-γ secretion in CD8+ T cells.In conclusion,Gln deficiency inhibits the effector function of CD8+ T cells by inducing ferroptosis,and promotes tumor growth.
