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

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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
    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
    Guangdong Provincial Key Lab of Translational Medicine in Lung Cancer)

  • 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)

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.

Suggested Citation

  • Zhenlin Yang & He Tian & Xiaowei Chen & Bozhao Li & Guangyu Bai & Qingyuan Cai & Jiachen Xu & Wei Guo & Shuaibo Wang & Yue Peng & Qing Liang & Liyan Xue & Shugeng Gao, 2024. "Single-cell sequencing reveals immune features of treatment response to neoadjuvant immunochemotherapy in esophageal squamous cell carcinoma," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-52977-0
    DOI: 10.1038/s41467-024-52977-0
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