The association of immune cell infiltration and prognostic value of tertiary lymphoid structures in gastric cancer

Ji-Shang Yu, Wei-Bin Huang, Yu-Hui Zhang, Jian Chen, Jin Li, Hua-Feng Fu,  Zhe-Wei Wei,  Yu-Long He

Abstract:

Tertiary lymphoid structures (TLS) are lymphoid aggregates in tumor tissues and their potential significance in clinical applications has not been fully elucidated in gastric cancer. We evaluated TLS and tumor-infiltrating immune cells using H&E and immunohistochemistry staining in the recruited patients with gastric cancer. The prognostic value of TLS was evaluated by Kaplan-Meier analysis and further validated using gene expression profiling. The alterations in gene mutation, copy number variance, and DNA methylation across the TLS signature subtypes were analyzed based on the Cancer Genome Atlas cohort. High TLS density was associated with improved overall survival and disease-free survival. A combination of TLS density and TNM stage obtained higher prognostic accuracy than the TNM stage alone. Tumors with high TLS density showed significantly higher infiltration of CD3+, CD8+, and CD20+ cells but lower infiltration of CD68+ cells. Transcriptomics analysis demonstrated that high TLS signature status was positively associated with the activation of inflammation-related and immune-related pathways. Multi-omics data showed a distinct landscape of somatic mutations, copy number variants, and DNA methylation across TLS signature subtypes. Our results indicated that TLS might link with enhanced immune responses, and represent an independent and beneficial predictor of resected gastric cancer. Multi-omics analysis further revealed key tumor-associated molecular alterations across TLS signature subtypes, which might help explore the potential mechanism of the interaction between TLS formation and cancer cells.