Investigation on the regulatory T cells signature and relevant Foxp3/STAT3 axis in esophageal cancer

Abstract

Background: Regulatory T cells (Tregs) have an important role in accelerating the immunosuppression of tumor. Tregs regulation is a hopeful strategy to improve the dismal prognosis of Esophageal cancer (EC), while its mechanisms have not yet been fully clarified.

Methods: To characterize the role of Tregs in EC, we comprehensively explored its prognostic value, clinical pathology partnership, related biological functions and potential mechanisms at transcriptome level. Through the integrated analysis of GEO and TCGA datasets, we comprehensively evaluated the Tregs infiltration patterns in EC patients. The correlation between Tregs infiltration and genomic characteristics, as well as biological functions were analyzed by a variety of computational algorithms.

Results: We observed that Tregs were significantly upregulated in EC and involved in various immune processes. According to TCGA and GEO transcriptional classification schemes, Tregs specific genes were observed to be highly expressed in tumor samples, as well as were closely associated with poor prognosis and worse clinical outcomes. In addition, EC patients can be stratified into high-risk and low-risk immune subgroups according to Tregs/macrophages infiltration level, and the results showed significant differences in tumor development, biological processes and probe gene expression pattern. The multi-variate analysis revealed that the interaction between STAT3 and Foxp3 was a potential prognostic signature of Tregs in EC, especially the modulation effect of STAT3 on Foxp3 expression, which has not been well studied in EC. We also identified that STAT3 and Foxp3 expression presented a high accuracy in predicting Tregs infiltration level in EC patients (AUC: 0.817; 95% CI: 0.756-0.878).

Conclusions: Our results revealed that Tregs have the potential to predict prognosis and tumor deterioration in EC patients. A comprehensive landscape of Tregs regulation mechanisms will help us interpret the immunosuppression of tumor microenvironment (TME) and novel strategies for EC immunotherapy.

Keywords: Esophageal cancer (EC); Foxp3; STAT3; Tregs; immune infiltration.