Immunogenomic landscape of hepatocellular carcinoma with immune cell stroma and EBV-positive tumor-infiltrating lymphocytes

Kang, Hyo Jeong; Oh, Ji-Hye; Chun, Sung-Min; Kim, Deokhoon; Ryu, Yeon‐Mi; Hwang, Hyeon-Shik; Kim, Sangjin; Cho, Eun Jeong; Lee, Hyeonjin; Shim, Ju Hyun; Sung, Chang‐Keun; Yu, Eunsil

doi:10.1016/j.jhep.2019.03.018

Cited by 40 publications

(40 citation statements)

References 36 publications

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“…Several recent studies have demonstrated that tumors could be divided into different subtypes according to the density and distribution of immune cells 26,27 . Herein, unsupervised clustering based on the immune density identified two subgroups with significantly different survival, where cluster 1 had a significantly better OS than cluster 2 ( P = .023) (Figure 2B).…”

Section: Resultsmentioning

confidence: 82%

The distribution of immune cells within combined hepatocellular carcinoma and cholangiocarcinoma predicts clinical outcome

Zheng

Tian

et al. 2020

Clinical & Translational Med

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Background This study aimed to investigate the clinical relevance of the immune microenvironment in patients with combined hepatocellular carcinoma and cholangiocarcinoma (cHCC‐ICC). Patients and Methods The density of tumor‐infiltrating CD3+, CD8+, CD163+, and Foxp3+ immune cells, as well as Programmed cell death 1, Programmed cell death‐ligand 1, and Tumor necrosis factor receptor superfamily member 4, was measured in the peritumor liver, tumor invasive margin, and intratumor subregions of 56 cHCC‐ICC by immunohistochemistry. The immune index was established to stratify patients. Prognostic significance of immune cell subsets and immune indices was evaluated. Results The distribution of immune cells was highly heterogeneous among different subregions of cHCC‐ICC. As compared with the hepatocellular carcinoma (HCC) component, the lower density of CD8+ T cells and higher intensity of Foxp3+ Tregs and immune checkpoints in the intrahepatic cholangiocarcinoma (ICC) component may indicate a stronger immune evasive ability of ICC. Based on clustering classification or a combination of random forest and lasso‐cox, two models of immune indices were established and both were identified as independent prognostic factors for cHCC‐ICC patients. The selected immune variables in the immune prognostic models derived from both HCC and ICC subregions, indicating that the prognosis of cHCC‐ICC patients was a complex interaction of both components. Conclusions The immune contexture was heterogeneous among different subregions of cHCC‐ICC patients and contributed differently to patient prognosis. Immune score based on the densities of immune cells might serve as a promising prognostic predictor for cHCC‐ICC patients.

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Section: Resultsmentioning

confidence: 82%

The distribution of immune cells within combined hepatocellular carcinoma and cholangiocarcinoma predicts clinical outcome

Zheng

Tian

et al. 2020

Clinical & Translational Med

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“…Others reported that the inactivated Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways we detected, namely, cytokine-cytokine receptor interaction, haematopoietic cell lineage, and Jak-STAT signalling pathway, were also altered in lung cancer subtypes 43 . Genes defining the primary immunodeficiency pathway were significantly enriched in hepatocellular carcinomas (HCCs) and correlated with the density of Epstein-Barr virus (EBV)-positive tumour-infiltrating lymphocytes (TILs) 44 , suggesting that the immunodeficiency pathway may reflect the degree of immune cell infiltration in tumours. Breast tumours lacking immune infiltration are associated with a poor prognosis 5 , consistent with our data showing that tumours with a high fraction of immune-related subclones were associated with improved OS.…”

Section: Discussionmentioning

confidence: 99%

Radiogenomic signatures reveal multiscale intratumour heterogeneity associated with biological functions and survival in breast cancer

et al. 2020

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Advanced tumours are often heterogeneous, consisting of subclones with various genetic alterations and functional roles. The precise molecular features that characterize the contributions of multiscale intratumour heterogeneity to malignant progression, metastasis, and poor survival are largely unknown. Here, we address these challenges in breast cancer by defining the landscape of heterogeneous tumour subclones and their biological functions using radiogenomic signatures. Molecular heterogeneity is identified by a fully unsupervised deconvolution of gene expression data. Relative prevalence of two subclones associated with cell cycle and primary immunodeficiency pathways identifies patients with significantly different survival outcomes. Radiogenomic signatures of imaging scale heterogeneity are extracted and used to classify patients into groups with distinct subclone compositions. Prognostic value is confirmed by survival analysis accounting for clinical variables. These findings provide insight into how a radiogenomic analysis can identify the biological activities of specific subclones that predict prognosis in a noninvasive and clinically relevant manner.

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“…EBV-associated tumors are often rich in lymphoid-like mesenchyme, and a recent study found EBVpositive was detected in 74.5% of hepatocellular carcinomas with immune cell stroma (HCC-IS). [418][419][420] This subtype of hepatocellular carcinoma has high-density EB-associated TIL infiltration and poorer RFS and OS characteristics, which may be related to the upregulation of CD28 co-stimulatory signals, T-cell receptors and other signaling pathways in HCC-IS, leading to CD8 + T-cell depletion and thus induced immune escape 420 in gastric cancer are silenced up to 75% EBVaGC exhibits a high frequency of DNA methylation, thus serving as a strategy for the virus to evade host immune regulation. [421][422][423] Immune-related genes (IRGS) in EBVaGC are silenced up to 75% by methylation, such as metallothionein-1 (MT1) and homologous box A (HOXA) clusters, thereby promoting EBV cleavage replication and subviral particle release, as well as KSHV cleavage reactivation.…”

Section: Ebv-related Vaccinesmentioning

confidence: 99%

Targeting the signaling in Epstein–Barr virus-associated diseases: mechanism, regulation, and clinical study

Cao

Xie

Shi

et al. 2021

Sig Transduct Target Ther

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Epstein–Barr virus-associated diseases are important global health concerns. As a group I carcinogen, EBV accounts for 1.5% of human malignances, including both epithelial- and lymphatic-originated tumors. Moreover, EBV plays an etiological and pathogenic role in a number of non-neoplastic diseases, and is even involved in multiple autoimmune diseases (SADs). In this review, we summarize and discuss some recent exciting discoveries in EBV research area, which including DNA methylation alterations, metabolic reprogramming, the changes of mitochondria and ubiquitin-proteasome system (UPS), oxidative stress and EBV lytic reactivation, variations in non-coding RNA (ncRNA), radiochemotherapy and immunotherapy. Understanding and learning from this advancement will further confirm the far-reaching and future value of therapeutic strategies in EBV-associated diseases.

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Immunogenomic landscape of hepatocellular carcinoma with immune cell stroma and EBV-positive tumor-infiltrating lymphocytes

Cited by 40 publications

References 36 publications

The distribution of immune cells within combined hepatocellular carcinoma and cholangiocarcinoma predicts clinical outcome

The distribution of immune cells within combined hepatocellular carcinoma and cholangiocarcinoma predicts clinical outcome

Radiogenomic signatures reveal multiscale intratumour heterogeneity associated with biological functions and survival in breast cancer

Targeting the signaling in Epstein–Barr virus-associated diseases: mechanism, regulation, and clinical study

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