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

Area of Science:

• Oncology
• Immunology
• Genomics

Background:

• Tertiary lymphoid structures (TLSs) are crucial in cancer prognosis and immunotherapy.
• Their clinical impact depends on spatial distribution and density within tumors.

Purpose of the Study:

• To investigate the role of TLS spatial localization in gastric cancer (GC).
• To analyze the cellular composition and interactions within different TLS subtypes.
• To develop a predictive signature for immunotherapy response in GC patients.

Main Methods:

• Integrated single-cell and spatial transcriptomic profiling of 30 GC specimens.
• Comparative analysis of intratumoral (iTLS), peritumoral (pTLS), and desert (dTLS) subtypes.
• Multimodal cell-cell interaction analysis and functional experiments.

Main Results:

• iTLS-rich tumors showed enrichment of CXCL13+ T lymphocytes, CXCR5+ B cells, activated dendritic cells, and high endothelial venule (HEV) cells.
• HEVs recruit and activate T lymphocytes via the CXCL13-ACKR1 pathway, promoting TLS formation.
• A novel single-cell/spatial TLS signature was developed, predicting immunotherapy outcomes.

Conclusions:

• TLS spatial localization significantly influences the tumor immune microenvironment in GC.
• Specific cellular components and interactions within iTLS are vital for anti-tumor immunity.
• The developed TLS signature holds predictive value for immunotherapy efficacy in GC.