AUTHOR=Jia Weili , Yao Qianyun , Wang Yanfang , Mao Zhenzhen , Zhang Tianchen , Li Jianhui , Nie Ye , Lei Xinjun , Shi Wen , Song Wenjie 

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

JOURNAL=Frontiers in Immunology

VOLUME=Volume 13 - 2022

YEAR=2022

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2022.1007426

DOI=10.3389/fimmu.2022.1007426

ISSN=1664-3224

ABSTRACT=BACKGROUND: Tertiary lymphoid structures have an effect on hepatocellular carcinoma, and the mechanism remains to be elucidated.
METHODS: Intratumoral TLS (iTLS) was classified in the TCGA-LIHC cohort using pathological sections from the Cancer digital slide archive. Univariate and multivariate Cox regression was performed to validate the effect of iTLS on patient OS, RFS, and DFS. The genes differentially expressed between the iTLS negative and positive groups were analyzed in combination with sequencing data. GSEA explored the signaling pathways affected by the differential genes. Random forest algorithm was used to identify the genes with the highest correlation with iTLS in the training set. multivariate logistic regression was used to build a model to predict iTLS in HCC samples. Spearman 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 by GSCA. Correlation R package was performed for gene ontology (GO), disease ontology (DO), and gene mutation analysis. GSCA was performed for drug sensitivity analysis. LASSO regression was used to build prognostic models and external data was used to validate the models.
RESULTS: There were 218 positive samples for iTLS compared to 146 negative. iTLS was significantly associated with better RFS and DFS according to Cox regression. Twenty signature genes were identified that were highly associated with iTLS positivity. GO and mutation analyses showed that the signature genes were associated with immunity. Most of the signature genes were sensitive to immune checkpoint inhibitors. The prognostic model based on the signature genes was an independent prognostic factor for OS.
Conclusions: The improvement of RFS in HCC by iTLS was not limited to the early but the whole period previously reported. iTLS promoted improvement of DFS in patients. Characteristic genes are closely related to the formation of iTLS and TLS chemokines in HCC. They are closely related to the body immunity in terms of cellular infiltration, biological functions, and signaling pathways. Most of them are sensitive to immune checkpoint inhibitors and their expression levels can affect prognosis.