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Down-regulation of EOMES drives T-cell exhaustion via abolishing EOMES-mediated repression of inhibitory receptors of T cells in liver cancer.

ABSTRACT: T-cell exhaustion is one of the hallmarks in cancer, but the mechanisms underlying T-cell dysregulation remains unclear. Here, we reported that down-regulation of transcription factor EOMES contributed to increased levels of inhibitory receptors in T cell among the tumour tissues and resulted in the poor prognosis of hepatocellular carcinoma (HCC). By analysing the correlation between EOMES in tumour-infiltrating T cells and the clinical features, we demonstrated that the EOMES was related to the advanced stage and poor prognosis of HCC. Further mechanistic studies revealed that the EOMES mainly expressed in the CD8⁺ T cells and were down-regulated in tumour samples. Moreover, we demonstrated that the EOMES directly bound at the transcriptional regulatory regions of the key inhibitory factors including PD-1, CTAL-4 and CD39, and lower levels of EOMES contributed to overexpression of these factors in T cells. Together, our studies provide new insight into the transcriptional deregulation of the inhibitory receptors on T cells during the tumorigenesis.

SUBMITTER: He H

PROVIDER: S-EPMC7810931 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Down-regulation of EOMES drives T-cell exhaustion via abolishing EOMES-mediated repression of inhibitory receptors of T cells in liver cancer.

He Hongwei H Yi Yong Y Cai Xiaoyan X Wang Jiaxing J Ni Xiaochun X Fu Yipeng Y Qiu Shuangjian S

Journal of cellular and molecular medicine 20201216 1

T-cell exhaustion is one of the hallmarks in cancer, but the mechanisms underlying T-cell dysregulation remains unclear. Here, we reported that down-regulation of transcription factor EOMES contributed to increased levels of inhibitory receptors in T cell among the tumour tissues and resulted in the poor prognosis of hepatocellular carcinoma (HCC). By analysing the correlation between EOMES in tumour-infiltrating T cells and the clinical features, we demonstrated that the EOMES was related to th ...[more]

PMID: 33325636

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Project description:In yeast physiology, a commonly used reference condition for many experiments, including those involving nitrogen catabolite repression (NCR), is growth in synthetic complete (SC) medium. Four SC formulations, SCCSH,1990, SCCSH,1994, SCCSH,2005, and SCME, have been used interchangeably as the nitrogen-rich medium of choice [Cold Spring Harbor Yeast Course Manuals (SCCSH) and a formulation in the methods in enzymology (SCME)]. It has been tacitly presumed that all of these formulations support equivalent responses. However, a recent report concluded that (i) TorC1 activity is downregulated by the lower concentration of primarily leucine in SCME relative to SCCSH. (ii) The Whi2-Psr1/2 complex is responsible for this downregulation. TorC1 is a primary nitrogen-responsive regulator in yeast. Among its downstream targets is control of NCR-sensitive transcription activators Gln3 and Gat1. They in turn control production of catabolic transporters and enzymes needed to scavenge poor nitrogen sources (e.g., Proline) and activate autophagy (ATG14). One of the reporters used in Chen et al. was an NCR-sensitive DAL80-GFP promoter fusion. This intrigued us because we expected minimal if any DAL80 expression in SC medium. Therefore, we investigated the source of the Dal80-GFP production and the proteomes of wild-type and whi2Δ cells cultured in SCCSH and SCME. We found a massive and equivalent reorientation of amino acid biosynthetic proteins in both wild-type and whi2Δ cells even though both media contained high overall concentrations of amino acids. Gcn2 appears to play a significant regulatory role in this reorientation. NCR-sensitive DAL80 expression and overall NCR-sensitive protein production were only marginally affected by the whi2Δ. In contrast, the levels of 58 proteins changed by an absolute value of log2 between 3 and 8 when Whi2 was abolished relative to wild type. Surprisingly, with only two exceptions could those proteins be related in GO analyses, i.e., GO terms associated with carbohydrate metabolism and oxidative stress after shifting a whi2Δ from SCCSH to SCME for 6 h. What was conspicuously missing were proteins related by TorC1- and NCR-associated GO terms.

Dataset Information

Down-regulation of EOMES drives T-cell exhaustion via abolishing EOMES-mediated repression of inhibitory receptors of T cells in liver cancer.

Publications

Down-regulation of EOMES drives T-cell exhaustion via abolishing EOMES-mediated repression of inhibitory receptors of T cells in liver cancer.

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