Yoshiaki Yanai

Analysis of the Antiviral Activities of Natural IFN-α Preparations and Their Subtype Compositions

Here we report on the antiviral effects of two commercially available natural interferon-alpha (IFN-alpha) preparations, their subtype compositions, and the effects of combinations of pairs of the subtypes on virally infected cells. Our results show that the antiviral effects of these preparations depend on the target cell and on the infecting virus. The component subtypes vary with the preparations, and combinations of pairs of IFN-alpha subtypes may have synergistic or competitive effects. Our results suggest that optimal preparations of synergistically acting subtypes may provide more therapeutic benefit to patients.

The anti-tumor activities of interferon (IFN)-α in chronic myelogenous leukaemia (CML)-derived cell lines depends on the IFN-α subtypes

Abstract Here we report on the anti-tumor effects of five interferon (IFN)-α subtypes, α1, α2, α5, α8, and α10 in chronic myelogenous leukaemia (CML)-derived cell lines. All of the CML cells can respond to IFN-α although the anti-tumor effects of IFN-α depend on the target cell and on the type of IFN-α subtype used. Proliferation assays showed that IFN-α8 was substantially more effective than the other four IFN-α subtypes. IFN-α8 was the most potent at upregulating immunomodulatory molecule expression while IFN-α1 was least potent. These data indicate in vitro distinctions between IFN-α subtypes that should be appreciated more in the clinic.

Characterization of the Antitumor Activities of IFN-α8 on Renal Cell Carcinoma Cells In Vitro

Interferon-alpha (IFN-alpha) has a number of therapeutic applications in the treatment of various human cancers and diseases of viral origin. IFN-alpha includes several subtypes, and little has been reported on the biologic properties of the individual subtypes. Here, we report on the individual antitumor effects of five IFN-alpha subtypes, alpha1, alpha2, alpha5, alpha8, and alpha10, against six renal cell carcinoma (RCC) cell lines in vitro. Among the subtypes, IFN-alpha8 most potently inhibited cell proliferation and delayed the G(1)/S transition. Synergistic induction of apoptosis was shown in two of the RCC cell lines when treated with the combination of IFN-alpha and IFN-gamma rather than with either IFN-alpha or IFN-gamma alone. IFN-alpha8 was most effective in the induction of apoptosis when combined with IFN-gamma. In addition, IFN-alpha8 had the strongest ability to upregulate HLA class II antigen expression in the subtypes examined. These data indicate that subtypes of IFN-alpha have disparate antitumor effects in vitro, and in vitro distinctions among the IFN-alpha subtypes should be appreciated more in clinical application.

Growth inhibitory effects of interferon-α subtypes vary according to human liver cancer cell lines

Background:  Interferon (IFN)‐α preparations used in the treatment of viral and neoplastic disease consist of single or multiple IFN‐α subtypes that may possess different biological activity, but there are no data on liver cancer cells.

EFFECTS OF INTERFERON-ALPHA SUBTYPES ON THE TH1/TH2 BALANCE IN PERIPHERAL BLOOD MONONUCLEAR CELLS FROM PATIENTS WITH HEPATITIS VIRUS INFECTION–ASSOCIATED LIVER DISORDERS

SummaryInterferon-alpha (IFN-α) has recently been shown to modulate in vitro T helper (Th) 1-driven responses in the peripheral blood mononuclear cells (PBMC) of patients with hepatitis B virus or C virus infection. In this study, we examined the in vitro effects of IFN-α subtypes (IFN-α1, −α2, −α5, −α8, and −α10) on the Th1/Th2 balance in PBMC obtained from patients with hepatitis virus infection-associated liver disorders and chronic hepatitis (CH), in comparison with the effect on healthy control volunteer PBMC. The Th1-type cell percentages and Th1/Th2 ratios were significantly higher in the PBMC of patients when compared with controls both before and after cultivation in vitro, with the IFN-α subtypes. The IFNα-5 induced an increase in the Th2-type cell percentages in both control and patient PBMC, resulting in that IFN-α5 lowered the Th1/Th2 ratio in patients with CH. Furthermore, statistical analysis revealed that IFN-α8 significantly promoted an increase in the Th1/Th2 ratios of PBMC from patients with CH and liver cirrhosis (LC) but not that of PBMC from patients with LC-hepatocellular carcinoma (HCC) and HCC. These findings imply that hepatitis virus infection and its disease status modify the effects of IFN-α subtypes on Th1 and Th2 immune balance in patients. Our findings should help to elucidate the mechanisms underlying successful IFN therapy for hepatitis virus infection and prevention of hepatocellular carcinogenesis.

Increased interferon alpha receptor 2 mRNA levels is associated with renal cell carcinoma metastasis

BackgroundInterferon-α (IFN-α) is one of the central agents in immunotherapy for renal cell carcinoma (RCC) and binds to the IFN-α receptor (IFNAR). We investigated the role of IFNAR in RCC.MethodsWe quantified IFNAR mRNA expression in paired tumor and non-tumor samples from the surgical specimens of 103 consecutive patients with RCC using a real-time reverse transcription polymerase chain reaction (RT-PCR), and IFNAR2 protein using Western blotting.ResultsThe absolute level of IFNAR1 and IFNAR2 mRNAs in tumor and non-tumor tissues did not correlate with the malignant and metastatic profiles. The relative yields of the PCR product from the tumor tissue to that from the corresponding non-tumor tissue (T/N) for the expression of IFNAR mRNAs were calculated. While the T/N ratio of IFNAR1 did not correlate with any factor, a high T/N ratio of IFNAR2 correlated with poor differentiation (P < 0.05), local invasion (P < 0.001), and metastasis (P < 0.0001). By multivariate analysis, a high T/N ratio of IFNAR2 predicted a shortened overall survival in all cases (P < 0.05) and a shorter disease-free survival in those without metastasis (M0; 68 cases, P < 0.05). Impressively, patients with a poorer response to IFN-α treatment had a higher IFNAR2 T/N ratio than those who had a good response (P < 0.05). IFNAR2c protein expression was higher in the primary tumors in patients with metastases (M1; 35 cases) compared to those without ( P < 0.0001).ConclusionIFNAR2 is associated with the progression of RCC.

Germline polymorphism of interferon-lambda3 is clinically associated with progression of renal cell carcinoma

Renal cell carcinoma (RCC) is an immunogenic tumor that shows a metabolic shift to aerobic glycolysis. The immune system can have opposing host-protective and tumor-promoting effects, and aerobic glycolysis suppresses antitumor immunity. In addition to immunostimulatory effect, increasing numbers of studies have revealed that interferon (IFN) is also involved in promoting immunosuppression. Since various single nucleotide polymorphisms (SNPs) can influence the outcome of anticancer therapy, we investigated SNPs for IFN-lambda3, a new member of IFN family, in 53 patients with metastatic RCC who underwent cytoreductive nephrectomy. The 16 patients who were heterozygous/homozygous for the minor alleles of SNPs for IFN-lambda3 had a significantly worse response to sequential vascular endothelial growth factor-targeting therapy (P = 0.0029) and shorter survival (P = 0.0033) compared with the 37 patients possessing the major alleles of SNPs for IFN-lambda3. In these 16 patients, the primary tumor showed elevated glucose uptake on positron emission tomography with [18F] fluorodeoxyglucose (P = 0.0160) and increased expression of programmed cell death 1 (PD-1)-ligand 1 (PD-L1) and phosphorylated serine/threonine kinase Akt (P = 0.0006 and P = 0.0043, respectively) compared to the tumors of the patients without these alleles. Since IFN-induced PD-L1 expression on either tumor cells or tumor-infiltrating mononuclear cells can trigger immunosuppression due to crosstalk between cancer cells and T cells, IFN-lambda3 polymorphism might be linked to the immunosuppressive effects of IFNs in cancer. Although this retrospective study lacks mechanistic insight, our findings suggest that IFN-lambda3 polymorphism might be relevant to the progression of RCC.

Interferon-related mental deterioration after craniotomy for removal of metastatic renal cancer

Abstract  Interferon‐related severe adverse events on the central nervous system are relatively rare, because interferon‐α (INF‐α) can not cross an intact blood–brain barrier. We experienced remarkable mental deterioration caused by INF‐α administration in a 43‐year‐old man with renal cell carcinoma after surgical removal of a metastatic brain tumor. We detected a high concentration of INF‐α in a cerebrospinal fluid sample, which was comparable to that in the serum at 24 h after the administration of INF‐α; 5 × 106 IU i.m., suggesting that the blood–brain barrier was damaged somehow by the craniotomy. The mental deterioration improved shortly after discontinuation of the INF‐α administration.