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Single-cell and spatial transcriptomics implicate a prognostic function of tertiary lymphoid structures in gastric cancer

Author

Listed:
  • Yanchun Wang

    (Beijing Institute of Biotechnology, Laboratory of Advanced Biotechnology)

  • Guangyu Zhang

    (The First Affiliated Hospital of Chongqing Medical University, Department of Rheumatology and Immunology, Center for Immune Ageing and Rejuvenation)

  • Xin Zhang

    (Chinese PLA General Hospital, Department of Pharmacy, Medical Supplies Center)

  • Gaoke Liu

    (Army Medical University, Department of Medical Genetics, College of Basic Medical Science)

  • Lihua Zhang

    (Chinese PLA General Hospital, Department of Pathology, Fourth Medical Center)

  • Lei Chen

    (The First Affiliated Hospital of Xi’an Jiaotong University, Department of Critical Care Nephrology and Blood Purification)

  • Shuli Sang

    (Beijing Institute of Biotechnology, Laboratory of Advanced Biotechnology)

  • Sheng Yao

    (Chinese PLA General Hospital, Department of General Surgery, First Medical Center)

  • Yang Fei

    (Chinese PLA General Hospital, Department of General Surgery, First Medical Center)

  • Zhichao Tian

    (Chinese PLA General Hospital, Department of General Surgery, First Medical Center)

  • Yu Zang

    (Chinese PLA General Hospital, Department of Pathology, Fourth Medical Center)

  • Hongwei Wang

    (Chinese PLA General Hospital, Department of Pathology, Fourth Medical Center)

  • Yiping Dong

    (Army Medical University, Department of Medical Genetics, College of Basic Medical Science)

  • Chunjie Liu

    (Beijing Institute of Biotechnology, Laboratory of Advanced Biotechnology)

  • Xizhao Chen

    (Chinese PLA General Hospital, Department of Nephrology, First Medical Center)

  • Yan Liu

    (Chinese PLA General Hospital, Department of Gastroenterology, First Medical Center)

  • Min Zhang

    (Chinese PLA General Hospital, Department of Nephrology, First Medical Center)

Abstract

Tertiary lymphoid structures (TLSs) have emerged as critical prognostic and immunotherapeutic indicators in cancer, with their clinical significance modulated by spatial distribution patterns and density. Here, we performed integrated single-cell and spatial transcriptomic profiling of 30 gastric cancer (GC) specimens stratified by TLS spatial localization patterns. Comparative analysis shows pronounced enrichment of CXCL13+ T lymphocytes (TLCs), CXCR5+ germinal center B lymphocytes (gc_B cells), LAMP3+CD80+ activated dendritic cells (DCs), and SELP+ACKR1+ high endothelial venule (HEV) cells within intratumoral-TLS (iTLS) rich tumors compared to peritumoral-TLS (pTLS) and desert-TLS (dTLS) tumor subtypes. Multimodal cell–cell interaction analysis and functional experiments demonstrate that HEV expressed VCAM1 and ICAM1 recruits and activates CXCL13+ TLC through the CXCL13-ACKR1 pathway, which promotes TLS formation via CXCL13-CXCR5-dependent crosstalk with B lymphocytes. We further develop a single-cell/spatial TLS signature that captures the cellular ecosystem of iTLS-containing tumor, demonstrating predictive value for immunotherapy outcomes in GC patients.

Suggested Citation

  • Yanchun Wang & Guangyu Zhang & Xin Zhang & Gaoke Liu & Lihua Zhang & Lei Chen & Shuli Sang & Sheng Yao & Yang Fei & Zhichao Tian & Yu Zang & Hongwei Wang & Yiping Dong & Chunjie Liu & Xizhao Chen & Ya, 2025. "Single-cell and spatial transcriptomics implicate a prognostic function of tertiary lymphoid structures in gastric cancer," Nature Communications, Nature, vol. 16(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-65421-8
    DOI: 10.1038/s41467-025-65421-8
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