Tertiary lymphoid structure stratifies glioma into three distinct tumor subtypes

Zhou, Xingwang; Li, Wenyan; Yang, Jie; Qi, Xiaolan; Chen, Yimin; Yang, Hua; Chu, Liangzhao

doi:10.18632/aging.203798

Cited by 8 publications

(6 citation statements)

References 38 publications

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“…( 21 ), the 40-TLS feature proposed by Zhou et al. ( 23 ), or the 50-TLS feature used by Wu et al. ( 24 ) ( Figure 7 ).…”

Section: Resultsmentioning

confidence: 99%

“…Previous studies used several genetic traits relevant to TLS to assess TLS in tissues. Results showed that these traits had different combinations, such as the 9-TLS trait ( 21 ), 12-TLS trait ( 22 ), 40-TLS trait ( 23 ), and 50-TLS trait ( 24 ). We selected these chemokines, developed correlation prediction models, and compared them with our model.…”

Section: Methodsmentioning

confidence: 99%

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Protective effect of tertiary lymphoid structures against hepatocellular carcinoma: New findings from a genetic perspective

et al. 2022

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BackgroundTertiary lymphoid structures (TLS) have an effect on hepatocellular carcinoma (HCC), but the underlying mechanism remains to be elucidated.MethodsIntratumoral TLS (iTLS) was classified in the Cancer Genome Atlas-Liver Hepatocellular Carcinoma (TCGA-LIHC) cohort using pathological sections from the Cancer Digital Slide Archive. Univariate and multivariate Cox regression analyses were performed to validate the effect of iTLS on overall survival (OS), relapse-free survival (RFS), and disease-free survival (DFS). The genes differentially expressed between the iTLS-negative and iTLS-positive groups were analyzed in combination with sequencing data. Gene set enrichment analysis (GSEA) was used to explore the signaling pathways affected by these differentially expressed genes. The random forest algorithm was used to identify genes with the highest correlation with the iTLS in the training set. Multivariate logistic regression was used to build a model to predict iTLS in tissue samples. Spearman’s correlation was used to analyze the relationship between TLS-associated chemokines and signature genes, and CIBERSORT was used to calculate immune infiltration scores. Copy number variation and its relationship with immune cell infiltration and signature genes were assessed using the gene set cancer analysis (GSCA). The Correlation R package was used for gene ontology (GO), disease ontology (DO), and gene mutation analyses. The GSCA was used for drug sensitivity analysis. LASSO regression was used to build prognostic models, and external data were used to validate the models.ResultsThere were 218 positive and 146 negative samples for iTLS. iTLS was significantly associated with better RFS and DFS according to Cox regression analysis. Twenty signature genes that were highly associated with iTLS positivity were identified. GO and mutation analyses revealed that the signature genes were associated with immunity. Most signature genes were sensitive to immune checkpoint inhibitors. Risk scores calculated using a characteristic gene-based prognostic model were found to be an independent prognostic factor for OS.ConclusionsThe improvement of RFS in HCC by iTLS was not limited to the early period as previously reported. iTLS improved DFS in patients. Characteristic genes are closely related to the formation of iTLS and TLS chemokines in HCC. These genes are closely related to immunity in terms of cellular infiltration, biological functions, and signaling pathways. Most are sensitive to immune checkpoint inhibitors, and their expression levels can affect prognosis.

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“…( 21 ), the 40-TLS feature proposed by Zhou et al. ( 23 ), or the 50-TLS feature used by Wu et al. ( 24 ) ( Figure 7 ).…”

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Protective effect of tertiary lymphoid structures against hepatocellular carcinoma: New findings from a genetic perspective

et al. 2022

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“…Hypercoagulability and thrombotic complications are common in patients with glioma ( 48 , 49 ). Several previous studies have reported that activation of CCC may be associated with the development of glioma ( 50 - 52 ). However, the specific mechanism of how the CCC is involved in glioma development and the mechanism of coagulation in gliomas has not been enclosed yet.…”

Section: Discussionmentioning

confidence: 99%

Complement and coagulation cascades are associated with prognosis and the immune microenvironment of lower-grade glioma

Yang,

Shen,

Yang

et al. 2024

Transl Cancer Res

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Background Abnormal coagulation is a common feature of glioma. There is a strong correlation between coagulation and the complement system, named complement and coagulation cascades (CCC). However, the role of CCC genes in lower-grade glioma (LGG) remains unclear. This study aimed to investigate the role of CCC genes in LGG. Methods In total, 5,628 differential expressed genes were identified between 498 LGG tissues from The Cancer Genome Atlas (TCGA) and 207 normal brain tissues from Genotype-Tissue Expression Project (GTEx). Among them, 20 overlapped CCC genes were identified as differentially expressed CCC genes. Then, comprehensive bioinformatics analysis was used to investigate the role of CCC genes in LGG; 271 LGG tissues from the Chinese Glioma Genome Atlas (CGGA) were used as the validation dataset. Cell Counting Kit-8 (CCK8) proliferation assay, colony formation assay, and wound healing assay were conducted to explore the anti-glioma effect of the sensitive drugs we predicted. Results We constructed a risk signature consisting of six CCC genes, including F2R , SERPINA1 , TFPI , C1QC , C2 , and C3AR1 . The CCC gene-based risk signature could accurately predict the prognosis of patients with LGG. In addition, we found that the JAK-STAT, NOD-like receptor, Notch, PI3K-Akt, and Rap1 signaling pathways might be activated and had crosstalk with CCC in the high-risk group. Our findings analyses demonstrated that samples in high- and low-risk groups had different immune landscapes. Moreover, patients in the high-risk group might have greater resistance to immunotherapy. We validated the accuracy of the risk signature in predicting immunotherapy response in two public immunotherapy cohorts, GSE135222 and GSE78220. By means of oncoPredict, MG-132, BMS-536924, PLX-4720, and AZD6482 were identified as potential sensitive drugs for high-risk patients, of which MG-132 was particularly recommended for high-risk patients. We performed in vitro experiments to explore the anti-glioma effect of MG-132, and the results demonstrated MG-132 could inhibit the proliferation and migration of glioma cells. Conclusions Our findings show that CCC genes are associated with the prognosis and immune infiltration of LGG and provide possible immunotherapeutic and novel chemotherapeutic strategies for patients with LGG based on the risk signature.

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“…Zhou et al. stratified glioma into three distinct tumor subtypes with the gene expression profile of TLS genes ( 28 ). The C subtype glioma with high immune infiltration was poor prognosis without immune checkpoint blockade therapy.…”

Section: Discussionmentioning

confidence: 99%

Glioblastoma with high O6-methyl-guanine DNA methyltransferase expression are more immunologically active than tumors with low MGMT expression

Kushihara,

Tanaka,

Kobayashi

et al. 2024

Front. Immunol.

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BackgroundGlioblastoma (GBM) is a highly lethal brain tumor. The effectiveness of temozolomide (TMZ) treatment in GBM is linked to the methylation status of O6-methyl-guanine DNA methyltransferase (MGMT) promoter. Patients with unmethylated MGMT promoter have limited treatment options available. Consequently, there is a pressing need for alternative therapeutic strategies for such patients.MethodsData, including transcriptomic and clinical information, as well as information on MGMT promoter methylation status in primary GBM, were obtained from The Cancer Genome Atlas (TCGA) (n=121) and Chinese Glioma Genome Atlas (CGGA) (n=83) datasets. Samples were categorized into high and low MGMT expression groups, MGMT-high (MGMT-H) and MGMT-low (MGMT-L) tumors. A comprehensive transcriptome analysis was conducted to explore the tumor-immune microenvironment. Furthermore, we integrated transcriptome data from 13 GBM patients operated at our institution with findings from tumor-infiltrating lymphocyte (TIL) cultures, specifically investigating their response to autologous tumors.ResultsGene signatures associated with various immune cells, including CD8 T cells, helper T cells, B cells, and macrophages, were noted in MGMT-H tumors. Pathway analysis confirmed the enrichment of immune cell-related pathways. Additionally, biological processes involved in the activation of monocytes and lymphocytes were observed in MGMT-H tumors. Furthermore, TIL culture experiments showed a greater presence of tumor-reactive T cells in MGMT-H tumors compared to MGMT-L tumors. These findings suggest that MGMT-H tumors has a potential for enhanced immune response against tumors mediated by CD8 T cells.ConclusionOur study provides novel insights into the immune cell composition of MGMT-H tumors, which is characterized by the infiltration of type 1 helper T cells and activated B cells, and also the presence of tumor-reactive T cells evidenced by TIL culture. These findings contribute to a better understanding of the immune response in MGMT-H tumors, emphasizing their potential for immunotherapy. Further studies are warranted to investigate on the mechanisms of MGMT expression and antitumor immunity.

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Tertiary lymphoid structure stratifies glioma into three distinct tumor subtypes

Cited by 8 publications

References 38 publications

Protective effect of tertiary lymphoid structures against hepatocellular carcinoma: New findings from a genetic perspective

Protective effect of tertiary lymphoid structures against hepatocellular carcinoma: New findings from a genetic perspective

Complement and coagulation cascades are associated with prognosis and the immune microenvironment of lower-grade glioma

Glioblastoma with high O6-methyl-guanine DNA methyltransferase expression are more immunologically active than tumors with low MGMT expression

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