Single-cell sequencing reveals immune features of treatment response to neoadjuvant immunochemotherapy in esophageal squamous cell carcinoma

Zhenlin Yang, He Tian, Xiaowei Chen, Bozhao Li, Guangyu Bai, Qingyuan Cai, Jiachen Xu, Wei Guo, Shuaibo Wang, Yue Peng, Qing Liang, Liyan Xue () and Shugeng Gao ()
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Zhenlin Yang: Chinese Academy of Medical Sciences and Peking Union Medical College
He Tian: Chinese Academy of Medical Sciences and Peking Union Medical College
Xiaowei Chen: Chinese Academy of Medical Sciences and Peking Union Medical College
Bozhao Li: National Center for Nanoscience and Technology
Guangyu Bai: Chinese Academy of Medical Sciences and Peking Union Medical College
Qingyuan Cai: Peking University
Jiachen Xu: Chinese Academy of Medical Sciences and Peking Union Medical College
Wei Guo: Chinese Academy of Medical Sciences and Peking Union Medical College
Shuaibo Wang: Chinese Academy of Medical Sciences and Peking Union Medical College
Yue Peng: Capital Medical University
Qing Liang: Chinese Academy of Medical Sciences and Peking Union Medical College
Liyan Xue: Chinese Academy of Medical Sciences and Peking Union Medical College
Shugeng Gao: Chinese Academy of Medical Sciences and Peking Union Medical College

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: Abstract Neoadjuvant immunochemotherapy (nICT) has dramatically changed the treatment landscape of operable esophageal squamous cell carcinoma (ESCC), but factors influencing tumor response to nICT are not well understood. Here, using single-cell RNA sequencing paired with T cell receptor sequencing, we profile tissues from ESCC patients accepting nICT treatment and characterize the tumor microenvironment context. CXCL13+CD8+ Tex cells, a subset of exhausted CD8+ T cells, are revealed to highly infiltrate in pre-treatment tumors and show prominent progenitor exhaustion phenotype in post-treatment samples from responders. We validate CXCL13+CD8+ Tex cells as a predictor of improved response to nICT and reveal CXCL13 to potentiate anti-PD-1 efficacy in vivo. Post-treatment tumors from non-responders are enriched for CXCL13+CD8+ Tex cells with notably remarkable exhaustion phenotype and TNFRSF4+CD4+ Tregs with activated immunosuppressive function and a significant clone expansion. Several critical markers for therapeutic resistance are also identified, including LRRC15+ fibroblasts and SPP1+ macrophages, which may recruit Tregs to form an immunosuppressive landscape. Overall, our findings unravel immune features of distinct therapeutic response to nICT treatment, providing a rationale for optimizing individualized neoadjuvant strategy in ESCC.

Date: 2024
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DOI: 10.1038/s41467-024-52977-0

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