Identification and characterization of prognosis-related genes in the tumor microenvironment of esophageal squamous cell carcinoma

Jun 24, 2021International immunopharmacology

Genes linked to outcomes in the environment around esophageal squamous cell cancer

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Circadian Biology on OpenScience ↗PubMed ↗DOI ↗

Abstract

A total of 410 differentially expressed genes were identified between high- and low-immune/stromal score groups in esophageal squamous cell carcinoma samples.

Among the 410 differentially expressed genes, 69 were linked to overall survival in patients with esophageal squamous cell carcinoma.
C3AR1 was identified as a core gene influencing the regulation of many genes within the tumor microenvironment.
C3AR1 showed a positive correlation with M2 macrophages and immune inhibitory molecules, such as TIM-3 and PD-1.
Higher expression levels of M2 macrophage markers CD163 and CD206 were observed in groups treated with TLQP-21, an agonist of C3AR1, compared to control groups.
C3AR1 may contribute to an immunosuppressive microenvironment by promoting the polarization of macrophages to the M2 phenotype, potentially leading to esophageal squamous cell carcinoma progression.

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BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is the main pathological subtype of esophageal cancer with high incidence and mortality. Immune and stromal cells in the tumor microenvironment (TME) profoundly affect the development of ESCC.

METHODS: In this study, we used the ESTIMATE algorithm to calculate the immune and stromal scores of ESCC samples in The Cancer Genome Atlas (TCGA) database. Next, we used the R package limma to identify differentially expressed genes (DEGs) from high- versus low-immune/stromal score groups and these DEGs were further utilized to analyze the functional annotations, protein-protein interaction (PPI) networks and overall survival of patients with ESCC. Finally, we identified the biological roles of core gene C3AR1 in the TME of ESCC using the TCGA database and in vitro experiments.

RESULTS: We obtained the immune and stromal scores of ESCC samples and further evaluated the impact of these scores on the prognosis and clinical parameters of patients with ESCC. Next, we identified 410 DEGs from high- versus low-immune/stromal score groups and to gain better understanding of the biological functions and characteristics of DEGs. Among these DEGs, 69 were correlated with the overall survival of patients with ESCC and C3AR1 was identified as a core gene for the regulation of most genes in the network. We found that C3AR1 was positively correlated with M2 macrophages and immune inhibitory molecules (T-cell immunoglobulin and mucin domain 3 (TIM-3), programmed cell death-1 (PD-1)), but not with M1 macrophages. We also observed a higher expression of CD163 and CD206, which were the markers for M2 macrophages in the TLQP-21 TFA (the agonist of C3AR1)groups than in the control groups.

CONCLUSION: Based on the ESTIMATE algorithm, we obtained and characterized prognosis-related genes in the TME of ESCC samples from the TCGA database. We have further revealed that C3AR1 may cause an immunosuppressive microenvironment by affecting the polarization of macrophages to M2 phenotype and lead to the progression of ESCC, which indicates that C3AR1 may be a potential target for immunotherapy.

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Identification and characterization of prognosis-related genes in the tumor microenvironment of esophageal squamous cell carcinoma

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