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Chemokine CXCL10 Modulates the Tumor Microenvironment of Fibrosis-Associated Hepatocellular Carcinoma.

ABSTRACT: Hepatocellular carcinoma (HCC) constitutes a devastating health burden. Recently, tumor microenvironment-directed interventions have profoundly changed the landscape of HCC therapy. In the present study, the function of the chemokine CXCL10 during fibrosis-associated hepatocarcinogenesis was analyzed with specific focus on its impact in shaping the tumor microenvironment. C57BL/6J wild type (WT) and Cxcl10 knockout mice (Cxcl10^-/-) were treated with diethylnitrosamine (DEN) and tetrachloromethane (CCl₄) to induce fibrosis-associated HCCs. Cxcl10 deficiency attenuated hepatocarcinogenesis by decreasing tumor cell proliferation as well as tumor vascularization and modulated tumor-associated extracellular matrix composition. Furthermore, the genetic inactivation of Cxcl10 mediated an alteration of the tumor-associated immune response and modified chemokine/chemokine receptor networks. The DEN/CCl₄-treated Cxcl10^-/- mice presented with a pro-inflammatory tumor microenvironment and an accumulation of anti-tumoral immune cells in the tissue. The most striking alteration in the Cxcl10^-/- tumor immune microenvironment was a vast accumulation of anti-tumoral T cells in the invasive tumor margin. In summary, our results demonstrate that CXCL10 exerts a non-redundant impact on several hallmarks of the tumor microenvironment and especially modulates the infiltration of anti-tumorigenic immune cells in HCC. In the era of microenvironment-targeted HCC therapies, interfering with CXCL10 defines a novel asset for further improvement of therapeutic strategies.

SUBMITTER: Brandt EF

PROVIDER: S-EPMC9329882 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature

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Chemokine CXCL10 Modulates the Tumor Microenvironment of Fibrosis-Associated Hepatocellular Carcinoma.

Brandt Elisa F EF Baues Maike M Wirtz Theresa H TH May Jan-Niklas JN Fischer Petra P Beckers Anika A Schüre Björn-Carsten BC Sahin Hacer H Trautwein Christian C Lammers Twan T Berres Marie-Luise ML

International journal of molecular sciences 20220723 15

Hepatocellular carcinoma (HCC) constitutes a devastating health burden. Recently, tumor microenvironment-directed interventions have profoundly changed the landscape of HCC therapy. In the present study, the function of the chemokine CXCL10 during fibrosis-associated hepatocarcinogenesis was analyzed with specific focus on its impact in shaping the tumor microenvironment. C57BL/6J wild type (WT) and Cxcl10 knockout mice (Cxcl10-/-) were treated with diethylnitrosamine (D ...[more]

PMID: 35897689

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Project description:IntroductionTumor purity takes on critical significance to the progression of solid tumors. The aim of this study was at exploring potential prognostic genes correlated with tumor purity in hepatocellular carcinoma (HCC) by bioinformatics analysis.MethodsThe ESTIMATE algorithm was applied for determining the tumor purity of HCC samples from The Cancer Genome Atlas (TCGA). The tumor purity-associated genes with differential expression (DEGs) were identified based on overlap analysis, weighted gene co-expression network analysis (WGCNA), and differential expression analysis. The prognostic genes were identified in terms of the prognostic model construction based on the Kaplan-Meier (K-M) survival analysis and Least Absolute Shrinkage and Selection Operator (LASSO) regression analyses. The expression of the above-described genes was further validated by the GSE105130 dataset from the Gene Expression Omnibus (GEO) database. We also characterized the clinical and immunophenotypes of prognostic genes. Gene set enrichment analysis (GSEA) was carried out for exploring the biological signaling pathway.ResultsA total of 26 tumor purity-associated DEGs were identified, which were involved in biological processes such as immune/inflammatory responses and fatty acid elongation. Ultimately, we identified ADCK3, HK3, and PPT1 as the prognostic genes for HCC. Moreover, HCC patients exhibiting higher ADCK3 expression and lower HK3 and PPT1 expressions had a better prognosis. Furthermore, high HK3 and PPT1 expressions and low ADCK3 expression resulted in high tumor purity, high immune score, high stromal score, and high ESTIMATE score. GSEA showed that the abovementioned prognostic genes showed a significant correlation with immune-inflammatory response, tumor growth, and fatty acid production/degradation.DiscussionIn conclusion, this study identified novel predictive biomarkers (ADCK3, HK3, and PPT1) and studied the underlying molecular mechanisms of HCC pathology initially.

Project description:Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and is the third leading cause of tumor-related mortality worldwide. In recent years, the emergency of immune checkpoint inhibitor (ICI) has revolutionized the management of HCC. Especially, the combination of atezolizumab (anti-PD1) and bevacizumab (anti-VEGF) has been approved by the FDA as the first-line treatment for advanced HCC. Despite great breakthrough in systemic therapy, HCC continues to portend a poor prognosis owing to drug resistance and frequent recurrence. The tumor microenvironment (TME) of HCC is a complex and structured mixture characterized by abnormal angiogenesis, chronic inflammation, and dysregulated extracellular matrix (ECM) remodeling, collectively contributing to the immunosuppressive milieu that in turn prompts HCC proliferation, invasion, and metastasis. The tumor microenvironment coexists and interacts with various immune cells to maintain the development of HCC. It is widely accepted that a dysfunctional tumor-immune ecosystem can lead to the failure of immune surveillance. The immunosuppressive TME is an external cause for immune evasion in HCC consisting of 1) immunosuppressive cells; 2) co-inhibitory signals; 3) soluble cytokines and signaling cascades; 4) metabolically hostile tumor microenvironment; 5) the gut microbiota that affects the immune microenvironment. Importantly, the effectiveness of immunotherapy largely depends on the tumor immune microenvironment (TIME). Also, the gut microbiota and metabolism profoundly affect the immune microenvironment. Understanding how TME affects HCC development and progression will contribute to better preventing HCC-specific immune evasion and overcoming resistance to already developed therapies. In this review, we mainly introduce immune evasion of HCC underlying the role of immune microenvironment, describe the dynamic interaction of immune microenvironment with dysfunctional metabolism and the gut microbiome, and propose therapeutic strategies to manipulate the TME in favor of more effective immunotherapy.

Project description:BackgroundImmunotherapy for liver cancer is used to rejuvenate tumor-infiltrating lymphocytes by modulating the immune microenvironment. Thus, early protective functions of T cell subtypes with tissue-specific residency have been studied in the tumor microenvironment (TME). We identified tumor-associated tissue-resident memory T (TA-TRM) cells in hepatocellular carcinoma (HCC) and characterized their molecular signatures.MethodsWe obtained single-cell RNA and single-cell TCR sequencing data from five patients with HCC. The heterogeneous characteristics of TRM cell subsets within the TME were then investigated and validated. Risk scores were calculated for survival analysis using significant core marker genes based on data from The Cancer Genome Atlas and the International Cancer Genome Consortium. The signaling pathways, trajectories, and clonal diversity of TA-TRM cells were investigated.ResultsWe characterized two TRM clusters (CD69+ and CD103+) that expressed unique signature genes and validated their similar molecular patterns in an independent dataset. Risk scores based on core gene expression in TA-TRM cells were associated with survival in both datasets. Trajectory analysis revealed that the two lineages followed different trajectory paths with distinct marker gene expression across pseudo-time. CD103+ TA-TRM cells showed diverse clonotypes and shared clonotypes with other cell groups. Lower clonal diversity and distinct signaling interactions were observed in the recurrent than in the non-recurrent samples. The CXCL13-CXCR3 interaction between CD103+ TA-TRM and regulatory T cells was observed only in the recurrent samples.ConclusionsWe identified two subtypes of TA-TRM cells in HCC and demonstrated their unique molecular signatures, relevance to survival, and distinct signaling networks according to recurrence. The study findings provide a better understanding of the molecular characteristics of TA-TRM cells in HCC and potential immunotherapeutic strategies.

Dataset Information

Chemokine CXCL10 Modulates the Tumor Microenvironment of Fibrosis-Associated Hepatocellular Carcinoma.

Publications

Chemokine CXCL10 Modulates the Tumor Microenvironment of Fibrosis-Associated Hepatocellular Carcinoma.

Similar Datasets

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