The hepatitis B virus-associated tumor microenvironment in hepatocellular carcinoma

Yang, Pengyuan; Markowitz, Geoffrey J.; Wang, Xiaofan

doi:10.1093/nsr/nwu038

Cited by 81 publications

(62 citation statements)

References 165 publications

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“…This process frequently results in a fibrotic and ultimately cirrhotic liver microenvironment; in this context, the cycling hepatocytes accumulate genetic alterations and eventually undergo malignant transformation [3]. This is in stark contrast with many other cancer types, in which the tissue from which the tumor arises is generally quite normal and functional [4, 5]. Indeed, 80 %–90 % of patients, whom have developed liver cancer after a long history of liver illness, have cirrhosis of the liver or late-stage fibrosis [2].…”

Section: Introductionmentioning

confidence: 99%

Inflammatory Models Drastically Alter Tumor Growth and the Immune Microenvironment in Hepatocellular Carcinoma

et al. 2015

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Initiation and progression of hepatocellular carcinoma (HCC) is intimately associated with a chronically diseased liver tissue. This diseased liver tissue background is a drastically different microenvironment from the healthy liver, especially with regard to immune cell prevalence and presence of mediators of immune function. To better understand the consequences of liver disease on tumor growth and the interplay with its microenvironment, we utilized two standard methods of fibrosis induction and orthotopic implantation of tumors into the inflamed and fibrotic liver to mimic the liver condition in human HCC patients. Compared to non-diseased controls, tumor growth was significantly enhanced under fibrotic conditions. The immune cells that infiltrated the tumors were also drastically different, with decreased numbers of natural killer cells but greatly increased numbers of immune-suppressive CD11b+ Gr1hi myeloid cells in both models of fibrosis. In addition, there were model-specific differences: Increased numbers of CD11b+ myeloid cells and CD4+ CD25+ T cells were found in tumors in the bile duct ligation model but not in the carbon tetrachloride model. Induction of fibrosis altered the cytokine production of implanted tumor cells, which could have farreaching consequences on the immune infiltrate and its functionality. Taken together, this work demonstrates that the combination of fibrosis induction with orthotopic tumor implantation results in a markedly different tumor microenvironment and tumor growth kinetics, emphasizing the necessity for more accurate modeling of HCC progression in mice, which takes into account the drastic changes in the tissue caused by chronic liver disease.

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Section: Introductionmentioning

confidence: 99%

Inflammatory Models Drastically Alter Tumor Growth and the Immune Microenvironment in Hepatocellular Carcinoma

et al. 2015

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“…Moreover, the presence and function of T‐infiltrating lymphocytes may be a prognostic marker in HCC patients . Therefore, a combination of depletion of Tregs and concomitant stimulation of effector T cells may represent an effective strategy to reduce HCC metastasis and recurrence . T‐cell activation using antibody blockade of the immune checkpoint programmed death receptor‐1 (PD‐1) has been successfully used for the treatment of late‐stage melanoma, and an anti‐PD‐1 antibody (pembrolizumab) was recently granted accelerated approval by the US Food and Drug Administration.…”

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confidence: 99%

CXCR4 inhibition in tumor microenvironment facilitates anti‐programmed death receptor‐1 immunotherapy in sorafenib‐treated hepatocellular carcinoma in mice

et al. 2015

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Sorafenib—a broad tyrosine kinase inhibitor—is the only approved systemic therapy for advanced hepatocellular carcinoma (HCC), but provides limited survival benefits. Recently, immunotherapy has emerged as a promising treatment strategy, but its role remains unclear in HCCs, which are associated with decreased cytotoxic CD8+ T-lymphocyte infiltration in both murine and human tumors. Moreover, we have shown in mouse models that after sorafenib treatment, intratumoral hypoxia is increased and may fuel evasive resistance. Using orthotopic HCC models, we now show that increased hypoxia after sorafenib treatment promotes immunosuppression, characterized by increased intratumoral expression of the immune checkpoint inhibitor programmed death-ligand 1 (PD-L1) and accumulation of T-regulatory cells and M2-type macrophages. We also show that the recruitment of the immunosuppressive cells is mediated in part by hypoxia-induced upregulation of stromal cell-derived 1 alpha (SDF1α). Inhibition of the SDF1α receptor (C-X-C receptor type 4 or CXCR4) using AMD3100 prevented the polarization toward an immunosuppressive microenvironment after sorafenib treatment, inhibited tumor growth, reduced lung metastasis, and improved survival. However, combination of AMD3100 and sorafenib did not significantly change cytotoxic CD8+ T-lymphocyte infiltration into HCC tumors and did not modify their activation status. In separate experiments, antibody blockade of the PD-L1 receptor PD-1 showed anti-tumor effects in treatment-naïve tumors in orthotopic (grafted and genetically engineered) models of HCC. However, anti-PD-1 antibody treatment had additional anti-tumor activity only when combined with sorafenib and AMD3100, and not when combined with sorafenib alone. Conclusion Anti-PD-1 treatment can boost anti-tumor immune responses in HCC models. When used in combination with sorafenib, this immunotherapy approach shows efficacy only with concomitant targeting of the hypoxic and immunosuppressive microenvironment with agents such as CXCR4 inhibitors.

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“…The current clinically used therapeutic agents for HBV are mainly IFNα and nucleos(t)ide analogues (Yuen and Lai, 2001;Liaw and Chu, 2009;Trepo et al, 2014); however, both agents have their limitations. IFNα, an immunomodulator, acts the enhance the immune response of the host to HBV antigens expressed on the surface of the hepatocytes, thereby causing or potentiating the lysis of infected hepatocytes (Yuen and Lai, 2001;Yang et al, 2014). However, the clinical application of IFNα is limited by its poor response, high cost, and adverse effects.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of hepatitis B virus replication by quercetin in human hepatoma cell lines

et al. 2015

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Hepatitis B virus (HBV) infection is one of the most serious and prevalent viral diseases in the world. Although several anti-HBV drugs have been used clinically, their side and adverse effects limit treatment efficacy. Therefore, it is necessary to identify novel potential anti-HBV agents. The flavonol quercetin has shown activity against some retroviruses, but its effect on HBV remains unclear. In the present study, quercetin was incubated with HepG2.2.15 cells, as well as HuH-7 cells transfected with an HBV plasmid. Quercetin was shown to significantly reduce Hepatitis B surface antigen (HBsAg) and Hepatitis B e antigen (HBeAg), secretion and HBV genomic DNA levels in both cell lines. In addition, co-incubation with lamivudine (3TC), entecavir (ETV), or adefovir (Ade) further enhanced the quercetin-induced inhibition of HBV replication. This inhibition was partially associated with decreased heat shock proteins and HBV transcription levels. The results indicate that quercetin inhibited HBV antigen secretion and genome replication in human hepatoma cell lines, which suggests that quercetin may be a potentially effective anti-HBV agent.

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The hepatitis B virus-associated tumor microenvironment in hepatocellular carcinoma

Cited by 81 publications

References 165 publications

Inflammatory Models Drastically Alter Tumor Growth and the Immune Microenvironment in Hepatocellular Carcinoma

Inflammatory Models Drastically Alter Tumor Growth and the Immune Microenvironment in Hepatocellular Carcinoma

CXCR4 inhibition in tumor microenvironment facilitates anti‐programmed death receptor‐1 immunotherapy in sorafenib‐treated hepatocellular carcinoma in mice

Inhibition of hepatitis B virus replication by quercetin in human hepatoma cell lines

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