An Immune Gene Expression Signature Associated With Development of Human Hepatocellular Carcinoma Identifies Mice That Respond to Chemopreventive Agents

Moeini, Agrin; Torrecilla, Sara; Tovar, Victoria; Montironi, Carla; Andreu-Oller, Carmen; Peix, Judit; Higuera, Mónica; Pfister, Dominik; Ramadori, Pierluigi; Pinyol, Roser; Solé, Manel; Heikenwälder, Mathias; Friedman, Scott L.; Sia, Daniela; Llovet, Josep M.

doi:10.1053/j.gastro.2019.07.028

Cited by 72 publications

(64 citation statements)

References 59 publications

(64 reference statements)

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“…In addition, wnt/β-catenin signaling was associated with immune-desert TME [37][38][39]. For example, Sia et al demonstrated that HCC samples with wnt/β-catenin activation showed signi cantly lower enrichment score for several immune signatures, especially T cells [40]. A preclinical study also demonstrated that βcatenin activation led to a defective recruitment of DCs and antigen-speci c T cells [18].…”

Section: Discussionmentioning

confidence: 99%

Wnt/β-catenin Inhibitor ICG-001 Enhances the Antitumor Efficacy of Radiotherapy by Increasing Radiation-induced DNA Damage and Improving Tumor Immune Microenvironment in Hepatocellular Carcinoma

Huang

Sheng

Xiao

et al. 2020

Preprint

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Background: Radiotherapy has a promising anti-tumor effect in hepatocellular carcinoma (HCC), depending on the its regulatory effects on both cancer cells and tumor immune microenvironment (TME). Wnt/β-catenin signaling pathway activation, which is one of the most common alterations in HCC patients, has been reported to induce radioresistance, and also create immunosuppressive TME. However, it is unclear whether inhibition of wnt/β-catenin pathway could enhance the treatment efficacy of radiotherapy. In this study, we aim to explore the effect of wnt/β-catenin inhibitor ICG-001 in combination with radiotherapy and the underlying mechanism in HCC.Methods: C57BL/6 and nude mouse subcutaneous tumor models were used to evaluate the efficacy of different treatment regimens in tumor growth control, tumor recurrence inhibition and survival improvement. Flow cytometry was performed to assess the alterations of tumor infiltrating lymphocytes (TILs). Radioresistance was investigated by clone formation assay and γ-H2AX measurements. Wnt/β-catenin and cGAS/STING pathway activation was detected by immunoblotting. Results: The addition of ICG-001 to radiotherapy exhibited better anti-tumor control efficacy in tumor-bearing C57BL/6 mice than nude mice, which suggested that ICG-001 had a critical role in activating TME. The comprehensive analysis of TILs revealed that compared with radiotherapy alone, the combination of ICG-001 with radiotherapy boosted the infiltration and IFN-γ production ability of TIL CD8+ T cells, meanwhile reduced the number of TIL Tregs. Moreover, mechanism study demonstrated that ICG-001 exerted a radiosensitizing effect on HCC cells, thus leading to stronger activation of cGAS/STING signaling pathway upon radiotherapy in vitro and in vivo. Utilization of STING inhibitor, C-176, significantly impaired the synergetic effect of ICG-001 with radiotherapy on tumor control and TME activation. Furthermore, combination therapy led to a stronger immunologic memory and lasting anti-tumor immunity than radiotherapy, thus preventing tumor relapse in HCC tumor-bearing mice.Conclusion: Our findings showed that ICG-001 increased radioresistance and improved TME upon radiotherapy in HCC. Compared with radiotherapy alone, the combination of ICG-001 with radiotherapy displayed better therapeutic efficacy in inhibiting tumor growth, prolonging survival, and preventing recurrence in tumor-bearing mice. These data indicated that ICG-001 might be a potential synergetic treatment for radiotherapy and radioimmunotherapy in HCC.

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Section: Discussionmentioning

confidence: 99%

Wnt/β-catenin Inhibitor ICG-001 Enhances the Antitumor Efficacy of Radiotherapy by Increasing Radiation-induced DNA Damage and Improving Tumor Immune Microenvironment in Hepatocellular Carcinoma

Huang

Sheng

Xiao

et al. 2020

Preprint

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“…With the development of the research, it is found that the tumor is a complete tissue with its own homeostasis (39) Comprehensive analysis showed that TMEScore was a prognostic biomarker for Luminal type B breast cancer, and high TMEScore was associated with poor prognosis. An immune-related gene expression pattern was identified in liver tissues of patients with early-stage HCC that associates with risk of HCC development (46). Zemek RM et al found that activation of a STAT1/NK axis in the tumor microenvironment could predicts response to immune checkpoint blockade, which suggest a biomarker-driven approach to patient management to establish whether a patient would benefit from treatment with sensitizing therapeutics before immune checkpoint blockade (47).…”

Section: Discussionmentioning

confidence: 99%

Tumor microenvironmental prognosis analysis and molecular labeling of immune-related genes in Luminal B type breast cancer

Gan¹,

Hu²,

Li³

et al. 2019

Preprint

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Background: Tumor microenvironment (TME) cells is one of the important elements, constitute the tumor tissues and in predicting tumor clinical results and treatment effect has the important significance of clinical pathology. However, a detailed map for prognostic landscape of TME in Luminal B breast cancer is still lacking. Methods: ownloaded the expression profile and clinical follow-up information of luminal B breast cancer from TCGA and GEO, and used CIBERSORT to evaluate the infiltration mode of TME in 209 patients, and constructed the molecular subtype of luminal B breast cancer based on TME, further evaluated the relationship between molecular subtype and prognosis. DESeq2 was used to analyze the differentially expressed genes among molecular subtypes of luminal B breast cancer, and cox multivariate regression analysis was used for feature selection to construct TME signature. Results: ased on the median value of TMEscore, the samples were divided into High TMEscore and Low TMEscroe, and the relationship with prognosis, clinical features, immune gene expression and genomic variation was further evaluated. Different TME cells have significant correlation in luminal B breast cancer. These TME cells stratified different clinical results of luminal B breast cancer, and further TMEscore was established by Cox regression analysis. High TME score is associated with poor prognosis. Meanwhile, this study showed that CXCL10, CXCL9, GZMB and other immune activation genes and PDCD1LG2 and other immune checkpoint genes have higher expression levels in high TME score, and the mutation frequency of TP53 gene was lower in risk-H than that in risk-L. Conclusion: In this study, we systematically evaluated the TME infiltration patterns of 209 TCGA luminal B breast cancer patients and developed the TME score approach. It was found that TME score is a powerful prognostic biomarker and predictor of response to immunocheckpoint inhibitors and provides a new strategy for luminal B breast cancer immunotherapy.

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“…The immune system can play vital roles in tumor initiation and progression, including HCC [5]. Various studies have demonstrated that aberrantly expressed immune-related genes (IRGs) are related to a high risk of HCC development and a poor clinical outcome [6][7][8]. Abnormal expression of the immune gene programmed death-ligand 1 (PD-L1) was found to be associated with vascular formation in HCC patients [7].…”

Section: Introductionmentioning

confidence: 99%

“…An IRG expression pattern in cirrhosis patients has been reported to be correlated with the risk of HCC occurrence. Mice with chronic liver inflammation administrated with nintedanib or aspirin and clopidogrel lost IRG expression pattern and exhibited an attenuation in tumor size [6]. Hence, systematic analysis and characterization of the immune-related genes is of great importance.…”

Section: Introductionmentioning

confidence: 99%

Identification and validation of an immune-related prognostic signature for hepatocellular carcinoma

Xia

Liu

2020

Preprint

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Background: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality. The immune system plays vital roles in HCC initiation and progression. The present study aimed to construct an immune-gene related prognostic signature (IRPS) for predicting the prognosis of HCC patients. Methods: Gene expression data were retrieved from The Cancer Genome Atlas database. Univariate Cox regression analysis was carried out to identify differentially expressed genes that associated with overall survival. The IRPS was established via Lasso and multivariate Cox regression analysis. Both Cox regression analyses were conducted to determine the independent prognostic factors for HCC. Next, the association between the IRPS and clinical-related factors were evaluated. The prognostic values of the IRPS were further validated using the International Cancer Genome Consortium (ICGC) dataset. Gene set enrichment analyses (GSEA) were conducted to understand the biological mechanisms of the IRPS. Results: A total of 62 genes were identified to be candidate immune-related prognostic genes. Transcription factors-immunogenes network was generated to explore the interactions among these candidate genes. According to the results of Lasso and multivariate Cox regression analysis, we established an IRPS and confirmed its stability and reliability in ICGC dataset. The IRPS was significantly associated with advanced clinicopathological characteristics. Both Cox regression analyses revealed that the IRPS could be an independent risk factor influencing the prognosis of HCC patients. The relationships between the IRPS and infiltration immune cells demonstrated that the IRPS was associated with immune cell infiltration. GSEA identified significantly enriched pathways, which might assist in elucidating the biological mechanisms of the IRPS. Furthermore, a nomogram was constructed to estimate the survival probability of HCC patients.Conclusions: The IRPS was effective for predicting prognosis of HCC patients, which might serve as novel prognostic and therapeutic biomarkers for HCC.

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An Immune Gene Expression Signature Associated With Development of Human Hepatocellular Carcinoma Identifies Mice That Respond to Chemopreventive Agents

Cited by 72 publications

References 59 publications

Wnt/β-catenin Inhibitor ICG-001 Enhances the Antitumor Efficacy of Radiotherapy by Increasing Radiation-induced DNA Damage and Improving Tumor Immune Microenvironment in Hepatocellular Carcinoma

Wnt/β-catenin Inhibitor ICG-001 Enhances the Antitumor Efficacy of Radiotherapy by Increasing Radiation-induced DNA Damage and Improving Tumor Immune Microenvironment in Hepatocellular Carcinoma

Tumor microenvironmental prognosis analysis and molecular labeling of immune-related genes in Luminal B type breast cancer

Identification and validation of an immune-related prognostic signature for hepatocellular carcinoma

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