Responders to neoadjuvant immune checkpoint inhibitor therapy in esophageal squamous cell carcinoma (ESCC) exhibit an increased abundance of cytotoxic CX3CR1⁺CD8⁺ T cells, according to a peer-reviewed study published in Nature Communications.
Researchers analyzed tumor samples from 52 ESCC patients enrolled in a phase 3 neoadjuvant trial to identify the mechanisms driving therapeutic sensitivity. The team tracked cellular shifts using single-cell RNA sequencing, T-cell receptor sequencing, and whole-exome sequencing.
Immune remodeling
Patients who responded to treatment showed clonal enrichment of cytotoxic CX3CR1⁺CD8⁺ T-cell clonotypes. Following therapy, these responder tumors also exhibited a reduced frequency and lower clonal dominance of exhausted CXCL13⁺CD8⁺ T-cell states. The accumulation of CX3CR1⁺CD8⁺ T cells was associated with CX3CL1–CX3CR1 signaling, a mechanism supported by functional experiments, mouse-model validation, and peripheral blood analyses.
Genomic data connected a higher cancer cell fraction mutation burden and neoantigen abundance to therapeutic response, which researchers noted was consistent with post-treatment immune editing. Variations in tumor epithelial differentiation states and stromal remodeling also correlated with clinical outcomes.
Study details
The research was conducted by scientists across the State Key Laboratory of Molecular Oncology, the Department of Thoracic Surgery at the Chinese Academy of Medical Sciences and Peking Union Medical College, and Beijing BTZJ Intelliseq Co. Ltd. Equal contributions came from Yahui Zhao, Ruixiang Zhang, Yang Li, Songming Liu, Cheng Liu, and Yuhao Wang.
The study received funding from the Shenzhen Medical Research Funds, the National Natural Science Foundation of China, the CAMS Innovation Fund for Medical Sciences, the Beijing Nova Program, and the Innovative Drug Research and Development National Science and Technology Major Project. The authors declared no competing interests.
