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Ectopic lymphoid structures function as microniches for tumor progenitor cells in hepatocellular carcinoma.

ABSTRACT: Ectopic lymphoid-like structures (ELSs) are often observed in cancer, yet their function is obscure. Although ELSs signify good prognosis in certain malignancies, we found that hepatic ELSs indicated poor prognosis for hepatocellular carcinoma (HCC). We studied an HCC mouse model that displayed abundant ELSs and found that they constituted immunopathological microniches wherein malignant hepatocyte progenitor cells appeared and thrived in a complex cellular and cytokine milieu until gaining self-sufficiency. The egress of progenitor cells and tumor formation were associated with the autocrine production of cytokines previously provided by the niche. ELSs developed via cooperation between the innate immune system and adaptive immune system, an event facilitated by activation of the transcription factor NF-κB and abolished by depletion of T cells. Such aberrant immunological foci might represent new targets for cancer therapy.

SUBMITTER: Finkin S

PROVIDER: S-EPMC4653079 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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Ectopic lymphoid structures function as microniches for tumor progenitor cells in hepatocellular carcinoma.

Finkin Shlomi S Yuan Detian D Stein Ilan I Taniguchi Koji K Weber Achim A Unger Kristian K Browning Jeffrey L JL Goossens Nicolas N Nakagawa Shigeki S Gunasekaran Ganesh G Schwartz Myron E ME Kobayashi Masahiro M Kumada Hiromitsu H Berger Michael M Pappo Orit O Rajewsky Klaus K Hoshida Yujin Y Karin Michael M Heikenwalder Mathias M Ben-Neriah Yinon Y Pikarsky Eli E

Nature immunology 20151026 12

Ectopic lymphoid-like structures (ELSs) are often observed in cancer, yet their function is obscure. Although ELSs signify good prognosis in certain malignancies, we found that hepatic ELSs indicated poor prognosis for hepatocellular carcinoma (HCC). We studied an HCC mouse model that displayed abundant ELSs and found that they constituted immunopathological microniches wherein malignant hepatocyte progenitor cells appeared and thrived in a complex cellular and cytokine milieu until gaining self ...[more]

PMID: 26502405

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Project description:BackgroundThe positive prediction of prognosis and immunotherapy within tertiary lymphoid structure (TLS) in cancerous tissue has been well demonstrated, including liver cancer. However, the relationship between TLS and prognosis in the peritumoral region of hepatocellular carcinoma (HCC) has received less attention. Few studies on whether TLS, as a typical representative of acquired immune cell groups, is associated with innate immune cells. The aim of this paper was to identify the prognostic role of peritumor TLS in HCC and to simply explore the relationship with neutrophils infiltration.MethodsThis study included cancerous and paracancerous tissue from 170 patients after surgical resection of HCC. TLS was examined and identified by pathological H&E examination, and the impact on prognosis was further classified by determination of total TLS area. Immunohistochemical staining of CD15+ neutrophils was also performed on half of the cases. The obtained results were validated by external public database, as TLS has been widely shown to be tagged with 12 chemokines.ResultsIn peritumoral tissue, the TLS- group had better overall survival (OS) and disease-free survival (DFS) outcomes compared with the TLS+ group. On the contrary, the intratumor TLS+ group showed better DFS outcomes. When further investigating the relationship between TLS area distribution and DFS, progressively worse prognosis was only found in the peritumor region with increasing TLS density (TLS- vs. TLSL vs. TLSH ). In addition, neutrophil infiltration increased in parallel with TLS density in the peritumoral region, which was not observed in the intratumoral region.ConclusionsTLS might have a dual prognostic role in different regions of HCC. The abundance of peritumoral TLS is an independent influence of DFS. The inconsistent correlation between neutrophils and corresponding TLS in different regions may indicate different pathways of immune aggregation and may serve as an explanation for the different prognosis of TLS, which needs to be specifically explored.

Project description: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.

Project description:BackgroundIntratumoral tertiary lymphoid structures (iTLS) in hepatocellular carcinoma (HCC) are associated with improved survival and may influence treatment decisions. However, their non-invasive detection remains challenging in HCC. We aim to develop a non-invasive model using baseline contrast-enhanced MRI to predict the iTLS status.MethodsA total of 660 patients with HCC who underwent surgery were retrospectively recruited from four centers between October 2015 and January 2023 and divided into training, internal test, and external validation sets. After features dimensionality and selection, corresponding features were used to construct transfer learning radiomic (TLR) models for diagnosing iTLS, and model interpretability was explored with pathway analysis in The Cancer Genome Atlas-Liver HCC. The performances of models were assessed using the area under the receiver operating characteristic curve (AUC). The log-rank test was used to evaluate the prognostic value of the TLR model. The combination therapy set of 101 patients with advanced HCC treated with first-line anti-programmed death 1 or ligand 1 plus antiangiogenic treatment between January 2021 and January 2024 was used to investigate the value of the TLR model for evaluating the treatment response.ResultsThe presence of iTLS was identified in 46.0% (n=308) patients. The TLR model demonstrated excellent performance in predicting the presence of iTLS in training (AUC=0.91, 95% CI: 0.87, 0.94), internal test (AUC=0.85, 95% CI: 0.77, 0.93) and external validation set (AUC=0.85, 95% CI: 0.81, 0.90). The TLR model-predicted iTLS group has favorable overall survival (HR=0.66; 95% CI: 0.48, 0.90; p=0.007) and relapse-free survival (HR=0.64; 95% CI: 0.48, 0.85; p=0.001) in the external validation set. The model-predicted iTLS status was associated with inflammatory response and specific tumor-associated signaling activation (all p<0.001). The proportion of treatment responders was significantly higher in the model-predicted group with iTLS than in the group without iTLS (36% vs 13.73%, p=0.009).ConclusionThe TLR model has indicated accurate prediction of iTLS status, which may assist in the risk stratification for patients with HCC in clinical practice.

Dataset Information

Ectopic lymphoid structures function as microniches for tumor progenitor cells in hepatocellular carcinoma.

Publications

Ectopic lymphoid structures function as microniches for tumor progenitor cells in hepatocellular carcinoma.

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