Abstract
Objective: Tertiary lymphoid structure (TLS), also known as ectopic lymphoid organs, are found in cancer, chronic inflammation, and autoimmune diseases. However, the heterogeneity of TLS in gliomas is unclear. Therefore, it is necessary to identify TLS differences and define TLS subtypes.Methods: The TLS gene profile of 697 gliomas from The Cancer Genome Atlas (TCGA) was used for consensus clustering to identify robust clusters, and the reproducibility of the stratification method was assessed in Chinese Glioma Genome Atlas (CGGA) cohort1, CGGA_cohort2, and GSE16011. Analyses of clinical characteristics, immune infiltration, and potential biological functions were performed for each subtype.Results: Three resulting clusters (A, B, and C) were identified based on consensus clustering on the gene expression profile of TLS genes. There was a significant prognostic difference among the clusters, with a shorter survival for C than B and A. In comparison with the A and B subtypes, the C subtype was significantly enriched in primary immunodeficiency, intestinal immune network for lgG production, antigen processing and presentation, natural killer cell-mediated cytotoxicity, complement and coagulation cascades, cytokine-cytokine receptor interaction, leukocyte transendothelial migration, and some immune-related diseases. The levels of 23 immune cell types were higher in the C subtype than in the A and B subtypes. Finally, we developed and validated a riskscore based on TLS subtypes with better performance of prognosis prediction.Conclusions: This study presents a new stratification method according to the TLS gene profile and highlights TLS heterogeneity in gliomas.
Highlights
Gliomas are common malignant tumors in the central nervous system [1]
We stratified gliomas into three subtypes according to the unsupervised clustering of Tertiary lymphoid structure (TLS) signature expression profiles
We found that the expression levels of CXCL2, CCL3, CCL4, CCL5, CCL8, CCL18, CXCL9, CXCL8, CXCL11, CXCL13, CD4, CCR5, CXCR3, CSF2, IGSF6, IL2RA, CD38, CD5, SDC1, GFI1, IL1R1, IL10, CCL20, IRF4, TRAF6, STAT5A, ICOS, SH2D1A, TIGIT, PDCD1 were higher in glioma tissues than in normal tissues (Figure 1D, p < 0.001); CXCL19, CXCL21, TNFRSF17, IL1R2, MS4A1, CD40, SGPP2, CD200, and FBLN7 were downregulated in glioma tissues (p < 0.001)
Summary
Gliomas are common malignant tumors in the central nervous system [1]. Glioma patients receive tumor resection following chemotherapy and radiotherapy [2], as well as tumor-treating fields [3], their prognosis remains poor. As a result, understanding the biological mechanism of glioma progression is crucial for glioma therapy. Immunotherapy, which is used to modulate lymphocytes to attack tumor cells and prevent tumor progression, has attracted considerable attention [4]. The efficacy of immunotherapy for glioblastoma patients is limited [5]. It is important to further analyze potential resistance factors and develop new treatment strategies
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