Evolution of genome and immunogenome in esophageal squamous cell carcinomas driven by neoadjuvant chemoradiotherapy

Background: Neoadjuvant chemoradiotherapy (NCRT) followed by surgery is a standard treatment for locally advanced esophageal squamous cell carcinomas (ESCCs). However, evolution of genome and immunogenome in ESCCs driven by NCRT remain incompletely elucidated. Methods We performed whole-exome sequencing of 51 ESCC tumors collected before and after NCRT, 36 of which were subjected to transcriptome sequencing. Results Clonal analysis identified clonal extinction in 13 ESCC patients wherein all pre-NCRT clones disappeared after NCRT, and clonal persistence in 9 patients wherein clones endured following NCRT. Clone-persistent patients showed higher pre-NCRT genomic intratumoral heterogeneity and worse prognosis than clone-extinct ones. In contrast to clone-extinct patients, clone-persistent patients demonstrated a high proportion of subclonal neoantigens within pre-treatment specimens. Transcriptome analysis revealed increased immune infiltrations and up-regulated immune-related pathways after NCRT, especially in clone-extinct patients. The number of T cell receptor-neoantigen interactions were higher in clone-extinct patients than clone-extinct ones. Decrease in T cell repertoire evenness positively correlated to the decreased number of clonal neoantigens after NCRT, especifically in clone-extinct patients. Conclusions We identified two prognosis-related clonal dynamic modes driven by NCRT in ESCCs. This study extended our knowledge in the field of ESCC genome and immunogenome evolutions driven by NCRT.