Discovery of a good responder subtype of esophageal squamous cell carcinoma with cytotoxic T-lymphocyte signatures activated by chemoradiotherapy

Abstract

Definitive chemoradiotherapy (CRT) is a less invasive therapy for esophageal squamous cell carcinoma (ESCC). Five-year survival rate of locally advanced ESCC patients by definitive CRT were 37%. We previously reported that tumor-specific cytotoxic T-lymphocyte (CTL) activation signatures were preferentially found in long-Term survivors. However, it is unknown whether the CTL activation is actually driven by CRT. We compared gene expression profiles among pre-and post-Treatment biopsy specimens of 30 ESCC patients and 121 pre-Treatment ESCC biopsy specimens. In the complete response (CR) cases, 999 overexpressed genes including at least 234 tumor-specific CTL-Activation associated genes such as IFNG, PRF1, and GZMB, were found in post-Treatment biopsy specimens. Clustering analysis using expression profiles of these 234 genes allowed us to distinguish the immune-Activated cases, designating them as I-Type, from other cases. However, despite the better CR rate in the I-Type, overall survival was not significantly better in both these 30 cases and another 121 cases. Further comparative study identified a series of epithelial to mesenchymal transition-related genes overexpressed in the early relapse cases. Importantly, the clinical outcome of CDH2-negative cases in the I-Type was significantly better than that of the CDH2-positive cases in the I-Type. Furthermore, NK cells, which were activated by neutrophils-producing S100A8/S100A9, and CTLs were suggested tocooperatively enhance the effect of CRT in the CDH2-negative I-Type. These results suggested that CTL gene activation may provide a prognostic advantage in ESCCs with epithelial characteristics.