Mitochondrial energy metabolism correlates with an immunosuppressive tumor microenvironment and poor prognosis in esophageal squamous cell carcinoma

Zewei Zhang; Gaowa Jin; Juan Zhao; Shuqin Deng; Feng Chen; Gaowa Wuyun; Lei Zhao; Quanfu Li

doi:10.1016/j.csbj.2023.08.022

Mitochondrial energy metabolism correlates with an immunosuppressive tumor microenvironment and poor prognosis in esophageal squamous cell carcinoma

Comput Struct Biotechnol J. 2023 Aug 24:21:4118-4133. doi: 10.1016/j.csbj.2023.08.022. eCollection 2023.

Authors

Zewei Zhang^{1

2

3}, Gaowa Jin⁴, Juan Zhao⁴, Shuqin Deng⁴, Feng Chen⁴, Gaowa Wuyun⁴, Lei Zhao^{1

2

3}, Quanfu Li⁴

Affiliations

¹ Department of Radiation Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China.
² State Key Laboratory of Oncology in South China, Guangzhou, China.
³ Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.
⁴ Department of Medical Oncology, Ordos Central Hospital, Ordos, China.

Abstract

Background: Reprogramming of mitochondrial energy metabolism (MEM) is an important hallmark of tumorigenesis and cancer progression. Currently, there are no studies that have examined MEM in the tumor microenvironment (TME) of esophageal squamous cell carcinoma (ESCC), and relevant drug targets have not yet been identified.

Methods: The ESCC single-cell transcriptome sequencing dataset, GSE145370, was analyzed, using the AUCell R package to screen for MEM-related genes in high-scoring cell populations. Monocle was used to infer cell differentiation and CellChat to analyze intercellular communication networks. Finally, transcription levels of prognostic genes were analyzed using a complementary DNA microarray from 15 patients with ESCC.

Results: A total of 121 MEM-related genes were differentially expressed in seven cell populations in the TME, and four high-scoring cell populations were identified. As a result, the MEM state of T cells is significantly different from that of macrophages and epithelial cells, and signaling communication between T cells and macrophages is the strongest. These findings suggest that immunosuppression is related to metabolic reprogramming. Additionally, marker genes of high-scoring cells and the top10 receptor-ligand pairs may become new targets for rebuilding immune cell metabolism. Furthermore, the 4-MEM gene risk signature had good predictive power for overall survival and drug sensitivity. MAP1LC3A, APOE, APPL1, and NDUFA are novel potential immunotherapeutic targets for remodeling the TME. Finally, teal-time quantitative PCR was used to verify APOE and MAP1LC3A expression.

Conclusion: MEM heterogeneity was observed in the immunosupressive TME of ESCC. Prognostic models based on MEM-related genes are helpful for screening early treatment patient groups and realizing personalized treatment. APOE and MAP1LC3A are potential target genes for the development of anti-ESCC drugs based on MEM-related genes.

Keywords: Crosstalk; Esophageal squamous cell carcinoma; Mitochondrial metabolism; Single-cell; Tumor microenvironment.