Sorafenib Prevents Escape from Host Immunity in Liver Cirrhosis Patients with Advanced Hepatocellular Carcinoma

Purpose. It has been reported that Th2 cytokines downregulate antitumor immunity, while activation of type T cells promotes antitumor immunity. The aim of this paper was to evaluate host immunity in liver cirrhosis (LC) patients with advanced hepatocellular carcinoma (aHCC) receiving sorafenib therapy.Methods. Forty-five adult Japanese LC patients received sorafenib for aHCC between 2009 and 2011 at our hospital. Sorafenib was administered at a dose of 200–800 mg/day for 4 weeks. Blood samples were collected before and after treatment.Results. Eleven patients were treated with sorafenib at 200 mg/day (200 group), 27 patients received sorafenib at 400 mg/day (400 group), and 7 patients were given sorafenib at 800 mg/day (800 group). There was no significant change in the percentage of Th1 cells after treatment in any group. However, the percentages of Th2 cells and regulatory T cells were significantly decreased after treatment in the 400 group and 800 group compared with before treatment, although there was no significant change after treatment in the 200 group.Conclusions. These results indicate that treatment with sorafenib might induce Th1 dominance and prevent the escape of tumor cells from the host immune system in LC patients with aHCC.

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Host Immunological Effects of Partial Splenic Embolization in Patients with Liver Cirrhosis

Journal of Immunology Research ◽

10.1155/2018/1746391 ◽

2018 ◽

Vol 2018 ◽

pp. 1-8 ◽

Cited By ~ 2

Author(s):

Yasushi Matsukiyo ◽

Hidenari Nagai ◽

Teppei Matsui ◽

Yoshinori Igarashi

Keyword(s):

Liver Cirrhosis ◽

Japanese Patients ◽

Serum Levels ◽

Treg Cells ◽

Host Immunity ◽

Th2 Cells ◽

Partial Splenic Embolization ◽

T Lymphocyte Subsets ◽

Splenic Embolization ◽

Significant Change

Purpose. Restoration of the balance between T lymphocyte subsets and between Th1/Th2 cytokines together with improvement of antitumor immunity has been reported after hepatosplenectomy in patients with liver cirrhosis (LC) and hepatocellular carcinoma (HCC). However, the detailed effects of partial splenic embolization (PSE) on host immunity are unknown. Accordingly, this study evaluated host immunity in patients with cirrhosis receiving PSE for thrombocytopenia.Methods. Twenty-three adult Japanese patients with cirrhosis and thrombocytopenia underwent PSE using straight coils at our hospital between 2010 and 2015. Blood samples were collected before PSE and 4 weeks after PSE.Results. The platelet counts were significantly higher 4 weeks after PSE compared with before PSE. The white blood cell count (neutrophils, lymphocytes, and monocytes) also increased significantly after PSE. Furthermore, Th1 cells and Th2 cells showed a significant increase at 4 weeks after PSE compared with before PSE, although there was no significant change of Treg cells. Moreover, serum levels of TNF-alpha, soluble TNF receptor I, and soluble Fas were significantly increased after PSE. There was no significant change of the Child-Pugh score.Conclusions. In patients with cirrhosis and thrombocytopenia, PSE not only promoted the recovery of leukopenia and thrombocytopenia but also induced activation of host immunity.

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Immune activation underlies a sustained clinical response to Yttrium-90 radioembolisation in hepatocellular carcinoma

Gut ◽

10.1136/gutjnl-2017-315485 ◽

2018 ◽

Vol 68 (2) ◽

pp. 335-346 ◽

Cited By ~ 36

Author(s):

Valerie Chew ◽

Yun Hua Lee ◽

Lu Pan ◽

Nurul J M Nasir ◽

Chun Jye Lim ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

T Cells ◽

Prediction Model ◽

Clinical Response ◽

Immune Activation ◽

Locally Advanced ◽

Advanced Hepatocellular Carcinoma ◽

Systemic Immune Activation ◽

Before And After ◽

Yttrium 90

ObjectivesYttrium-90 (Y90)-radioembolisation (RE) significantly regresses locally advanced hepatocellular carcinoma and delays disease progression. The current study is designed to deeply interrogate the immunological impact of Y90-RE, which elicits a sustained therapeutic response.DesignTime-of-flight mass cytometry and next-generation sequencing (NGS) were used to analyse the immune landscapes of tumour-infiltrating leucocytes (TILs), tumour tissues and peripheral blood mononuclear cells (PBMCs) at different time points before and after Y90-RE.ResultsTILs isolated after Y90-RE exhibited signs of local immune activation: higher expression of granzyme B (GB) and infiltration of CD8+ T cells, CD56+ NK cells and CD8+ CD56+ NKT cells. NGS confirmed the upregulation of genes involved in innate and adaptive immune activation in Y90-RE-treated tumours. Chemotactic pathways involving CCL5 and CXCL16 correlated with the recruitment of activated GB+CD8+ T cells to the Y90-RE-treated tumours. When comparing PBMCs before and after Y90-RE, we observed an increase in tumour necrosis factor-α on both the CD8+ and CD4+ T cells as well as an increase in percentage of antigen-presenting cells after Y90-RE, implying a systemic immune activation. Interestingly, a high percentage of PD-1+/Tim-3+CD8+ T cells coexpressing the homing receptors CCR5 and CXCR6 denoted Y90-RE responders. A prediction model was also built to identify sustained responders to Y90-RE based on the immune profiles from pretreatment PBMCs.ConclusionHigh-dimensional analysis of tumour and systemic immune landscapes identified local and systemic immune activation that corresponded to the sustained response to Y90-RE. Potential biomarkers associated with a positive clinical response were identified and a prediction model was built to identify sustained responders prior to treatment.

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Changes of host immunity in relation to efficacy in liver cirrhosis patients with advanced hepatocellular carcinoma treated by intra-arterial chemotherapy

Cancer Chemotherapy and Pharmacology ◽

10.1007/s00280-008-0866-8 ◽

2008 ◽

Vol 64 (2) ◽

pp. 271-277 ◽

Cited By ~ 5

Author(s):

Kouichi Momiyama ◽

Hidenari Nagai ◽

Yasukiyo Sumino

Keyword(s):

Hepatocellular Carcinoma ◽

Liver Cirrhosis ◽

Host Immunity ◽

Advanced Hepatocellular Carcinoma

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Influence of Sorafenib on Host Immunity in Patients with Liver Cirrhosis With Advanced Hepatocellular Carcinoma Stratified by Etiology

Anticancer Research ◽

10.21873/anticanres.13333 ◽

2019 ◽

Vol 39 (4) ◽

pp. 2183-2191 ◽

Cited By ~ 3

Author(s):

HIDENARI NAGAI ◽

TAKANORI MUKOZU ◽

KOJIRO KOBAYASHI ◽

MAKOTO AMANUMA ◽

NAOYUKI YOSHIMINE ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Liver Cirrhosis ◽

Host Immunity ◽

Advanced Hepatocellular Carcinoma

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The use of single-agent sorafenib in the treatment of advanced hepatocellular carcinoma patients with underlying Child-Pugh B liver cirrhosis

Cancer ◽

10.1002/cncr.27543 ◽

2012 ◽

Vol 118 (21) ◽

pp. 5293-5301 ◽

Cited By ~ 42

Author(s):

Joanne Chiu ◽

Yuen Fong Tang ◽

Tzy-Jyun Yao ◽

Ashley Wong ◽

Hilda Wong ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Liver Cirrhosis ◽

Single Agent ◽

Advanced Hepatocellular Carcinoma

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The Promise of Immunotherapy in the Treatment of Hepatocellular Carcinoma

American Society of Clinical Oncology Educational Book ◽

10.1200/edbk_175230 ◽

2017 ◽

pp. 311-317 ◽

Cited By ~ 1

Author(s):

Anthony El-Khoueiry

Keyword(s):

Hepatocellular Carcinoma ◽

Cell Therapy ◽

Antitumor Immunity ◽

Advanced Hepatocellular Carcinoma ◽

Checkpoint Inhibition ◽

Cell Infiltrate ◽

Immune Mediated ◽

Viral Therapy ◽

Excellent Candidate ◽

Tumor Environment

Advanced hepatocellular carcinoma (HCC) has presented a therapeutic challenge. Despite its heterogeneity, which is partially related to its various etiologies, it frequently arises in a background of chronic inflammation, which makes it a potentially excellent candidate for immunotherapeutic approaches. There is evidence of antitumor immunity in HCC as manifested by the cell infiltrate and its association with prognosis, the presence of tumor-associated antigens, and the reports of immune-mediated spontaneous regressions. However, both the liver itself and the tumor environment possess a diverse armamentarium of mechanisms that suppress antitumor immunity. Here, we describe the rationale for immunotherapy in HCC and discuss the emerging clinical data from various immunotherapeutic approaches including checkpoint inhibition, cell therapy, oncolytic viral therapy, and various combinatorial approaches. We also highlight the potential for various modalities to be adapted across different stages of the disease.

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