Interferon-lambda (IFNL) germline variations and their significance for HCC and PDAC progression: an analysis of The Cancer Genome Atlas (TCGA) data

Huschka, Henriette; Mihm, Sabine

doi:10.1186/s12885-020-07589-4

Cited by 4 publications

(3 citation statements)

References 24 publications

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“…Therefore, the fact a large amount of IFN-l is produced by DCs in response to STING activation warrants further investigation in the realms of cancer immunotherapy. However, as the IFN-l locus has been shown to be polymorphic in a subset of cancer patients and patients suffering from infectious diseases (8,29,65,66), moving forward, polymorphisms and differences in IFN-l gene expression will need to be taken into account when considering clinical STING immunotherapeutic approaches (29,35,67,68).…”

Section: Discussionmentioning

confidence: 99%

Discordance in STING-Induced Activation and Cell Death Between Mouse and Human Dendritic Cell Populations

et al. 2022

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Stimulator of Interferon Genes (STING) is a cytosolic sensor of cyclic dinucleotides (CDNs). The activation of dendritic cells (DC) via the STING pathway, and their subsequent production of type I interferon (IFN) is considered central to eradicating tumours in mouse models. However, this contribution of STING in preclinical murine studies has not translated into positive outcomes of STING agonists in phase I & II clinical trials. We therefore questioned whether a difference in human DC responses could be critical to the lack of STING agonist efficacy in human settings. This study sought to directly compare mouse and human plasmacytoid DCs and conventional DC subset responses upon STING activation. We found all mouse and human DC subsets were potently activated by STING stimulation. As expected, Type I IFNs were produced by both mouse and human plasmacytoid DCs. However, mouse and human plasmacytoid and conventional DCs all produced type III IFNs (i.e., IFN-λs) in response to STING activation. Of particular interest, all human DCs produced large amounts of IFN-λ1, not expressed in the mouse genome. Furthermore, we also found differential cell death responses upon STING activation, observing rapid ablation of mouse, but not human, plasmacytoid DCs. STING-induced cell death in murine plasmacytoid DCs occurred in a cell-intrinsic manner and involved intrinsic apoptosis. These data highlight discordance between STING IFN and cell death responses in mouse and human DCs and caution against extrapolating STING-mediated events in mouse models to equivalent human outcomes.

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Section: Discussionmentioning

confidence: 99%

Discordance in STING-Induced Activation and Cell Death Between Mouse and Human Dendritic Cell Populations

et al. 2022

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“…Reading out IFNL genotypes from controlled access sequencing reads was performed as described previously [24]. In brief, whole-exome sequencing (WXS) reads of nonmalignant tissue (code 11A) or peripheral blood leucocyte (code 10A) were cut down to the region spanning the IFNL gene cluster (chr19: 39,230,000-39,300,000) by using the BAM slice tool.…”

Section: Reading Out Ifnl Genotypesmentioning

confidence: 99%

Hepatic IFNL4 Gene Activation in Hepatocellular Carcinoma Patients with Regard to Etiology

Huschka

Mihm

2021

IJMS

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Hepatocellular carcinoma (HCC) is a malignancy with a leading lethality. The etiology is quite diverse, ranging from viral infections to metabolic disorders or intoxications, and associates with specific somatic mutational patterns and specific host immunological phenotypes. Particularly, hepatitis C virus (HCV)-infected liver is featured by an activation of interferon (IFN)-stimulated genes (ISGs; IFN signature), which we suppose is driven by type III IFNL4. Taking advantage of the TCGA collection of HCC patients of various different etiologies, this study aimed at validating our previous findings on hepatic IFNL4 gene activation in HCV infection in an independent and larger cohort of patients with advanced liver disease. In a cohort of n = 377 cases, the entirety of the sequencing data was used to assess the IFNL genotypes, and the cases were stratified for etiology. The number of IFNL4 transcripts within nonmalignant and malignant tissues was found to be more abundant in patients with HCV or HCV/HBV infections when compared to other risk factors. Moreover, in patients with HCV infection as a risk factor, a close, positive relationship was found between ISG activation and the number of functional IFNL4 transcripts. Data on this independent TCGA sample support the concept of an IFNL4-dependent HCV-driven activation of hepatic ISGs. In addition to that, they add to the understanding of etiology-related host immunological phenotypes in HCC.

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“…Hepatocellular carcinoma (HCC), the most commonly seen type of primary hepatic carcinoma, is one of the most commonly seen malignancies in clinical practice, and its related mortality ranks the third among malignant tumors ( 1 ). Most patients with HCC have no obvious symptoms at the early stage but are already in the middle and advanced stages when they are treated, and the overall prognosis is still poor ( 3 ). It was found that the great rate of cancer relapse and metastases was the main factor leading to unsatisfactory prognoses of HCC sufferers.…”

Section: Introductionmentioning

confidence: 99%

Effects of Tumor-Derived DNA on CXCL12-CXCR4 and CCL21-CCR7 Axes of Hepatocellular Carcinoma Cells and the Regulation of Sinomenine Hydrochloride

Shen

Li²,

Li³

et al. 2022

Front. Oncol.

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Currently, chemokines and their receptors, CXCL12-CXCR4 and CCL21-CCR7 axes, are deemed vital factors in the modulation of angiogenesis and are crucial for the growth and development of liver cancer. Tumor-derived DNA can be recognized by immune cells to induce an autoimmune response. In this study, we demonstrated the mechanism of tumor-derived DNA on the CXCL12-CXCR4 and CCL21-CCR7 axes of hepatocellular carcinoma (HCC) cells and the regulatory effect of sinomenine hydrochloride. Tumor-derived DNA was separated from HCCLM cell lines. Tumor-derived DNA was transfected into SK-Hep1 cells by Lipofectamine 2000. We found that sinomenine hydrochloride reduced the expression of CXCR4, CXCR12, CCR7, and CCL21 in HCC cells, suppressed the growth and invasion of HCC cells, and increased apoptosis. In contrast to the controls, the protein expressions of CXCR4, CXCL12, CCR7, CCL21, P-ERK1/2, MMP-9, and MMP-2 in SK-Hep1 cells were significantly increased after transfection of tumor-derived DNA, while the increase was reversed by sinobine hydrochloride. Acid sinomenine interferes with tumor-derived DNA and affects ERK/MMP signaling via the CXCL12/CXCR4 axis in HCC cells. CXCR4 siRNA and CCR7 siRNA attenuated tumor-derived DNA activation of ERK1/2/MMP2/9 signaling pathways in HCC cells. CXCR4-oe and CCR7-OE enhance the stimulation of erK1/2/MMP2/9 signaling pathway by tumor-derived DNA in HCC cells. Tumor-derived DNA reduced apoptosis and increased invasion of SK-Hep1 cells by CXCL12-CXCR4 axis and CCL21-CCR7 axis, and sinobine hydrochloride reversed this regulation. These results strongly suggest that tumor-derived DNA can increase the growth and invasion of oncocytes via the upregulation of the expression of CXCL12-CXCR4 and CCL21-CCR7 axis and through ERK1/2/MMP2/9 signaling pathway in HCC cells, and sinobine hydrochloride can inhibit this signaling pathway, thus inhibiting HCC cells. These results provide new potential therapeutic targets for blocking the progression of HCC induced by CXCL12-CXCR4 axis and CCL21-CCR7.

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Interferon-lambda (IFNL) germline variations and their significance for HCC and PDAC progression: an analysis of The Cancer Genome Atlas (TCGA) data

Cited by 4 publications

References 24 publications

Discordance in STING-Induced Activation and Cell Death Between Mouse and Human Dendritic Cell Populations

Discordance in STING-Induced Activation and Cell Death Between Mouse and Human Dendritic Cell Populations

Hepatic IFNL4 Gene Activation in Hepatocellular Carcinoma Patients with Regard to Etiology

Effects of Tumor-Derived DNA on CXCL12-CXCR4 and CCL21-CCR7 Axes of Hepatocellular Carcinoma Cells and the Regulation of Sinomenine Hydrochloride

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