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ABSTRACT: Myeloid-derived suppressor cells (MDSCs) are known as key immune regulators in various human malignancies, and it is reported that CD14(+)HLA-DR(-/low) MDSCs are increased in hepatocellular carcinoma (HCC) patients. However, the host factors that regulate the frequency and the effect on the prognosis of HCC patients are still unclear. We investigated these issues and clarified the relationships between a feature of MDSCs and host factors in HCC patients. We examined the frequency of MDSCs in 123 HCC patients, 30 chronic liver disease patients without HCC, and 13 healthy controls by flow cytometric analysis. The relationships between the clinical features and the frequency of MDSCs were analyzed. In 33 patients who received curative radiofrequency ablation (RFA) therapy, we examined the impact of MDSCs on HCC recurrence. The frequency of MDSCs in HCC patients was significantly increased. It was correlated with tumor progression, but not with the degree of liver fibrosis and inflammation. In terms of serum cytokines, the concentrations of IL-10, IL-13, and vascular endothelial growth factor were significantly correlated with the frequency of MDSCs. In HCC patients who received curative RFA therapy, the frequency of MDSCs after treatment showed various changes and was inversely correlated with recurrence-free survival time. The frequency of MDSCs is correlated with tumor progression, and this frequency after RFA is inversely correlated with the prognosis of HCC patients. Patients with a high frequency of MDSCs after RFA should be closely followed and the inhibition of MDSCs may improve the prognosis of patients.
Cancer Immunology and Immunotherapy 06/2013; · 3.70 Impact Factor
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Yoshiko Takata,
Yasunari Nakamoto,
Akiko Nakada,
Takeshi Terashima,
Fumitaka Arihara, Masaaki Kitahara,
Kaheita Kakinoki,
Kuniaki Arai,
Taro Yamashita,
Yoshio Sakai,
Tatsuya Yamashita,
Eishiro Mizukoshi,
Shuichi Kaneko
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ABSTRACT: The purpose of this study was to assess the properties of CD4+CD25(high/low/negative) T cell subsets and analyze their relation with dendritic cells (DCs) in patients with hepatocellular carcinoma (HCC). In HCC patients, the prevalence of CD45RO+ cells in CD4+CD25(high) T cells was increased and associated with higher frequencies of plasmacytoid DCs. Larger proportions of this T cell subset were detected in the patients with larger tumor burdens. These results suggest that increased frequencies of the CD45RO+ subset in CD4+CD25(high) Tregs in HCC patients may establish the immunosuppressive environment cooperatively with tolerogenic plasmacytoid DCs to promote disease progression of liver cancer.
Cancer letters 08/2011; 307(2):165-73. · 4.86 Impact Factor
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ABSTRACT: Meniere's disease is a common inner ear disease with an incidence of 15 to 50 per 100,000 population. Since Meniere's disease is thought to be triggered by an immune insult to the inner ear, we examined intraendolymphatic sac application of steroids as a new therapeutic strategy for intractable Meniere's disease.
Prospective randomized controlled study.
Between 1996 and 2005, we enrolled and assigned 197 intractable Meniere's patients to three groups in a randomized controlled trial: Group I (G-I)- patients who underwent endolymphatic sac drainage and steroid-instillation; Group II (G-II)-those who underwent endolymphatic sac drainage without steroid-instillation; and Group III (G-III)-those who declined endolymphatic sac drainage. Definitive spells and hearing in all three groups were determined for 2 to 7 years after treatment.
According to the 1995 American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS) criteria, 2-year results demonstrated that vertigo was completely controlled in 88.0% of patients in G-I (n = 100), 85.1% of patients in G-II (n = 47), and 8.0% in G-III (n = 50). Statistically, G-I = G-II>G-III. Hearing was improved in 49.0% of patients in G-I, 31.9% in G-II, and 6.0% in G-III (G-I>G-II>G-III). Results after 7 years showed that vertigo was completely controlled in 78.8% of patients in G-I, 79.2% in G-II, and 25.0% in G-III (G-I = G-II>G-III). Hearing improved in 36.5% of patients in G-I, 8.3% in G-II, and 0.0% in G-III (G-I>G-II = G-III).
From non-surgical observation in G-III for at least 7 years after treatment, steroids instilled into endolymphatic sac in G-I patients significantly improved hearing in intractable Meniere's patients, more so than endolymphatic sac drainage without steroids in G-II patients.
The Laryngoscope 05/2008; 118(5):854-61. · 1.75 Impact Factor
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ABSTRACT: Tumor recurrence rates remain high after curative treatments for hepatocellular carcinoma (HCC). Immunomodulatory agents, including chemokines, are believed to enhance the antitumor effects of tumor cell apoptosis induced by suicide gene therapy. We therefore evaluated the immunomodulatory effects of a bicistronic recombinant adenovirus vector (rAd) expressing both HSV thymidine kinase and MCP-1 on HCC cells. Using an athymic nude mouse model (BALB/c-nu/nu), primary s.c. tumors (HuH7; human HCC cells) were completely eradicated by rAd followed by treatment with ganciclovir. The same animals were subsequently rechallenged with HCC cells, tumor development was monitored, and the recruitment or activation of NK cells was analyzed immunohistochemically or by measuring IFN-gamma mRNA expression. Tumor growth was markedly suppressed as compared with that in mice treated with a rAd expressing the HSV thymidine kinase gene alone (p < 0.001). Suppression of tumor growth was associated with the elevation of serum IL-12 and IL-18. During suppression, NK cells were recruited exclusively, and Th1 cytokine gene expression was enhanced in tumor tissues. The antitumor activity, however, was abolished either when the NK cells were inactivated with anti-asialo GM1 Ab or when anti-IL-12 and anti-IL-18 Abs were administered. These results indicate that suicide gene therapy, together with delivery of MCP-1, eradicates HCC cells and exerts prolonged NK cell-mediated antitumor effects in a model of HCC, suggesting a plausible strategy to prevent tumor recurrence.
The Journal of Immunology 01/2007; 178(1):574-83. · 5.79 Impact Factor
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Yasunari Nakamoto,
Eishiro Mizukoshi, Masaaki Kitahara,
Fumitaka Arihara,
Yoshio Sakai,
Kaheita Kakinoki,
Yui Fujita,
Yohei Marukawa,
Kuniaki Arai,
Tatsuya Yamashita,
Naofumi Mukaida,
Kouji Matsushima,
Osamu Matsui,
Shuichi Kaneko
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ABSTRACT: Despite curative locoregional treatments for hepatocellular carcinoma (HCC), tumour recurrence rates remain high. The current study was designed to assess the safety and bioactivity of infusion of dendritic cells (DCs) stimulated with OK432, a streptococcus-derived anti-cancer immunotherapeutic agent, into tumour tissues following transcatheter hepatic arterial embolization (TAE) treatment in patients with HCC. DCs were derived from peripheral blood monocytes of patients with hepatitis C virus-related cirrhosis and HCC in the presence of interleukin (IL)-4 and granulocyte-macrophage colony-stimulating factor and stimulated with 0.1 KE/ml OK432 for 2 days. Thirteen patients were administered with 5 × 106 of DCs through arterial catheter during the procedures of TAE treatment on day 7. The immunomodulatory effects and clinical responses were evaluated in comparison with a group of 22 historical controls treated with TAE but without DC transfer. OK432 stimulation of immature DCs promoted their maturation towards cells with activated phenotypes, high expression of a homing receptor, fairly well-preserved phagocytic capacity, greatly enhanced cytokine production and effective tumoricidal activity. Administration of OK432-stimulated DCs to patients was found to be feasible and safe. Kaplan-Meier analysis revealed prolonged recurrence-free survival of patients treated in this manner compared with the historical controls (P = 0.046, log-rank test). The bioactivity of the transferred DCs was reflected in higher serum concentrations of the cytokines IL-9, IL-15 and tumour necrosis factor-α and the chemokines CCL4 and CCL11. Collectively, this study suggests that a DC-based, active immunotherapeutic strategy in combination with locoregional treatments exerts beneficial anti-tumour effects against liver cancer. © 2010 The Authors. Clinical and Experimental Immunology © 2010 British Society for Immunology.
