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

Neoadjuvant chemoradiotherapy (NCRT) followed by surgery is a standard treatment for locally advanced esophageal squamous cell carcinomas (ESCCs). However, the evolution of genome and immunogenome in ESCCs driven by NCRT remains incompletely elucidated. We performed whole‐exome sequencing of 51 ESCC tumors collected before and after NCRT, 36 of which were subjected to transcriptome sequencing. 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. The clone‐persistent patients showed higher pre‐NCRT genomic intratumoral heterogeneity and worse prognosis than the clone‐extinct ones. In contrast to the clone‐extinct patients, the 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 the clone‐extinct patients. The number of T cell receptor–neoantigen interactions was higher in the clone‐extinct patients than in the clone‐persistent ones. The decrease in T cell repertoire evenness positively correlated to the decreased number of clonal neoantigens after NCRT, especially in the clone‐extinct patients. In conclusion, we identified two prognosis‐related clonal dynamic modes driven by NCRT in ESCCs. This study extended our knowledge of the ESCC genome and immunogenome evolutions driven by NCRT. What's new? Genetic changes and clonal evolution can influence the likelihood of cancer returning after treatment, and neoadjuvant chemoradiotherapy (NCRT) may impact those genetic changes. Here, the authors investigated how tumor heterogeneity affected treatment responses in esophageal squamous cell carcinoma (ESCC). They performed whole‐exome and transcriptome sequencing on the tumor and the immune microenvironment before and after NCRT, and clonal analysis to see whether clones persisted after treatment. They identified two clonal dynamics that affected prognosis after NCRT. This study is the first to systematically describe clonal dynamics during NCRT in this way, and these findings could help identify determinants of treatment responses.