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The Functionalities and Clinical Significance of Tumor-Infiltrating Immune Cells in Esophageal Squamous Cell Carcinoma.

ABSTRACT: Tumor-infiltrating immune cells have been implicated in the tumorigenesis and progression of esophageal squamous cell carcinoma (ESCC). However, the functionalities and clinical significance of immune cells remain largely unveiled. In this study, the gene expression data from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) were extracted. The relative infiltrating levels were estimated by single-sample gene set enrichment analysis. Some cytotoxic immune cells were attenuated, and resting cytotoxic immune cells were accumulated in ESCC. Remarkably, we also observed that infiltrating levels of macrophage M2 and resting natural killer (NK) cells were increased in nonresponders of CRT, and T cells that had anticancer activities such as activated memory CD4 and T helper 2 (Th2) cells were significantly reduced in ESCC tissues of the nonresponders. Moreover, the high infiltrations of the resting natural killer (NK) and dendritic cell (DC) were observed to result in a shorter overall survival in ESCC. Consistently, high expression of immune checkpoint genes, CTLA4 and HAVCR2, was associated with poor prognosis. Furthermore, STAT5B, a key transcription factor, as well as its target genes, involved in the regulation of T cells, was significantly downregulated in ESCC, especially subgroup I, indicating that downregulation of STAT5B might be associated with reduced T cell-mediated anticancer activity. In conclusion, the present study significantly improved our understanding of the regulatory roles of immune cells in ESCC.

SUBMITTER: Zhang J

PROVIDER: S-EPMC8490060 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background Esophageal cancer (EC) is a highly aggressive malignancy that is classified as esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC). Infiltrating stromal/immune cells, a major component of the tumor immune microenvironment (TIME), have prognostic significance in various cancers. Methods In this study we investigated genes and immune factors in the tumor microenvironment (TME) of ESCC and EAC that can serve as prognostic biomarkers. Stromal and immune scores were calculated using the Estimation of Stromal and Immune Cells in Malignant Tumor Tissues Using Expression Data (ESTIMATE) algorithm based on gene expression profiles of patient-derived tumor tissues in The Cancer Genome Atlas database. The correlation between ESTIMATE scores and survival rates in EC were analyzed. A comparison of high and low stromal/immune score groups revealed multiple differentially expressed genes (DEGs) as candidate prognostic genes; their role in immune-related biological processes was evaluated by functional and protein-protein interaction (PPI) network analyses, and the genes were validated using Gene Expression Omnibus datasets. Additionally, 22 tumor-infiltrating immune cell (TIIC) subsets were analyzed using the CIBERSORT algorithm. Results Median stromal score was higher whereas immune score was lower in ESCC than in EAC (both P<0.01). Stromal score was lower in female as compared to male ESCC patients (P<0.05), and was significantly correlated with T stage (P<0.05). In EAC, median immune score was higher in female as compared to male patients (P<0.05) and was correlated with tumor-node-metastasis stage (P<0.05). The identified DEGs were mainly involved in lymphocyte (especially T-lymphocyte) activation and carbohydrate binding. Moreover, the levels of infiltrating resting-stage dendritic cells, CD8+ T cells, naïve B cells, activated mast cells, and resting memory CD4+ T cells were significantly correlated with EC prognosis (P<0.05). Conclusions The immune microenvironment of ESCC and EAC are quite different. We have found genes with prognostic value in multiple tumor databases.

Project description:Objective:Increasing evidence has indicated an association between immune cells infiltration in LSCC and clinical outcome. The aim of this research was tantamount to comprehensively investigate the effect of 22 tumor infiltrating immune cells (TIICs) on the prognosis of LSCC patients. Methods:In our research, the CIBERSORT algorithm was utilized to calculate the proportion of 22 TIICs in 502 cases from the TCGA cohort. Cases with a CIBERSORT P-value of <0.05 were kept for further study. Using the CIBERSORT algorithm, we first investigated the difference of immune infiltration between normal tissue and LSCC in 22 subpopulations of immune cells. Kaplan-Meier analysis was used to analyze the effect of 22 TIICs on the prognosis of LSCC. An immune risk score model was constructed based on TIICs correlated with LSCC-related recurrence. Multivariate cox regression analysis was used to investigate whether the immune risk score was an independent factor for prognosis prediction of LSCC. Nomogram was under construction to comprehensively predict the survival rate of LSCC. Results:The results of the different analysis showed that except of memory B cells, naive CD4+T cells, T cells and activated NK cells, the remaining immune cells all had differential infiltration in normal tissues and LSCC (p < 0.05). Kaplan-Meier analysis revealed two immune cells statistically related to LSCC-related recurrence, including activated mast cells and follicular helper T cells. Immune risk score model was constructed based on three immune cells including resting memory CD4+T cells, activated mast cells and follicular helper T cells retained by forward stepwise regression analysis. The Kaplan-Meier curve indicated that patients in the high-risk group linked to poor outcome (P = 8.277e-03). ROC curve indicated that the immune risk score model was reliable in predicting recurrence risk (AUC = 0.614). Multivariate cox regression analysis showed that the immune risk score model was just an independent factor for prognosis prediction of LSCC (HR = 2.99, 95% CI [1.65-5.40]; P = 0.0002). The nomogram model combined immune risk score and clinicopathologic parameter score to predict 3-year survival in patients with LSCC. Conclusions:Collectively, tumor-infiltrating immune cells play a major role in the prognosis of LSCC.

Project description:The present authors previously identified a novel candidate tumor suppressor gene, zinc finger protein 750 (ZNF750), in esophageal squamous cell carcinoma (ESCC) (1). The present study aimed to clarify the clinical significance of ZNF750 expression in ESCC. The association between ZNF750 DNA mutation status and the mRNA expression was examined by whole exome sequence analysis and quantitative reverse transcription polymerase chain reaction (RT-qPCR). The expression of ZNF750 in 76 patients with ESCC (Kyushu University Beppu Hospital) was measured using immunohistochemistry and RT-qPCR. Using this dataset, the association between ZNF750 mRNA expression and clinicopathological factors was examined. Additionally, survival analysis was performed using datasets from the Kyushu University Beppu Hospital and The Cancer Genome Atlas (TCGA). The biological effects of ZNF750 expression were explored using gene set enrichment analysis (GSEA) and were validated using datasets from the Cancer Cell Line Encyclopedia (CCLE) and the Kyushu University Beppu Hospital. ZNF750 expression analyses demonstrated that ZNF750 mRNA expression was lower in patients with the DNA mutations compared with those without the mutations (P<0.05), and ZNF750 expression was downregulated in tumor tissues compared with normal tissues (P<0.00005). In the clinicopathological analysis, the low ZNF750 expression group exhibited a higher incidence of undifferentiated histology (P<0.05) compared with the high expression group. The low ZNF750 expression group exhibited a poorer prognosis in the Kyushu and TCGA datasets (P<0.0005 and P<0.05, respectively). GSEA indicated that ZNF750 expression was significantly correlated with epithelial differentiation in ESCC. This was confirmed using the datasets from CCLE and the Kyushu University Beppu Hospital by analyzing the levels of small proline rich protein 1A mRNA, an epithelial differentiation-associated gene. In conclusion, the results of the present study suggested that ZNF750 serves a role as a tumor suppressor; potentially via regulating epithelial differentiation and that it may be a promising biomarker of poor outcomes in ESCC.

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The Functionalities and Clinical Significance of Tumor-Infiltrating Immune Cells in Esophageal Squamous Cell Carcinoma.

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