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.

A phase 2 study of spartalizumab (PDR001) among patients with recurrent or metastatic esophageal squamous cell carcinoma (KCSG HN18-17, K-MASTER project 12)

“… 30 , 31 Increased infiltration of immune cells, irrespective of the biomarker, displayed a trend toward an improved prognosis. As earlier reports suggest, higher density of PD-1, 32 FOXP3, 33 CD3, 34 CD4, 27 and CD8 25 positive immune cell infiltration exhibited improved efficacy against PD-1 blockade (Supplementary Fig. S8C-L).…”

Advances in Foxp3+ regulatory T cells (Foxp3+ Treg) and key factors in digestive malignancies

“…This helps to upregulate Foxp3 expression in ESCC. By increasing Foxp3 expression through STAT3 modification of Foxp3+Treg transcription process, activating the STAT3/Foxp3 signaling pathway within ESCC tissue hinders macrophage phagocytosis and increases Foxp3+Treg immunosuppressive activity, which helps ESCC evade the body’s immune response ( 26 ). Furthermore, upon recognition of its receptor ST2, IL-33 attracts a significant number of Foxp3+Tregs to congregate in the stroma of ESCC, thereby initiating the IL-33/ST2/Foxp3+Treg/COX-2/PGs regulatory pathway, encouraging Foxp3+Treg secretion of cyclooxygenase-2 (COX-2) and enabling the conversion and production of prostaglandins (PGs).…”

Cathepsin L promotes oesophageal squamous cell carcinoma development and may be associated with tumour-associated macrophages

“…The tumour microenvironment (TME) has a significant impact on tumour development, owing to its ability to suppress the immune system by inhibiting and depleting T, B, and natural killer cells. This action weakens the defense system of the body against tumours, enabling them to evade the immune system [ [4] , [5] , [6] , [7] ]. Numerous studies have demonstrated an association between multiple resistant cell populations in the TME and development, invasion, and metastasis [ [8] , [9] , [10] ].…”