伊藤 弘康

AIM: Chronic hepatitis B virus (HBV) infection remains a major cause of liver cirrhosis and hepatocellular carcinoma. NASVAC is a therapeutic vaccine containing hepatitis B surface antigen (HBsAg) and hepatitis B core antigen (HBcAg), which has shown clinical potential to induce loss of HBsAg and acquisition of anti-HBs antibodies. Indoleamine 2,3-dioxygenase (IDO), an enzyme that degrades tryptophan into kynurenine, plays a key role in viral persistence by suppressing effector T cell activity and promoting immunoregulatory pathways. This study aimed to elucidate the role of IDO in modulating immune responses to NASVAC. METHODS: Wild-type and IDO knockout (KO) mice were immunized with NASVAC, and some wild-type mice received an IDO inhibitor. Serum amino acids and anti-HBc and anti-HBs titers, cellular immune responses, splenic CD4/CD8 T cell ratios, and IL-2 production from splenocytes were assessed. Additionally, pretreatment and posttreatment serum samples from NASVAC clinical trial were analyzed for tryptophan and kynurenine levels to assess their association with the efficacy of vaccination. RESULTS: Genetic deletion of IDO markedly enhanced NASVAC-induced humoral and cellular immune responses in mice, whereas pharmacological inhibition partially increased cellular responses. NASVAC treatment modulated the splenic CD4/CD8 ratio, with more pronounced effects in IDO-KO mice. In human participants, lower pretreatment serum kynurenine level was associated with successful acquisition of anti-HBs following NASVAC administration. CONCLUSIONS: These findings suggest that IDO activity negatively regulates both humoral and cellular immune responses to NASVAC. Modulation or suppression of IDO may potentially enhance the therapeutic efficacy of NASVAC, and serum kynurenine may represent a predictive biomarker for treatment outcomes in chronic HBV infection. REGISTRY AND THE REGISTRATION NO. OF THE STUDY/TRIAL: The clinical trial was registered in the UMIN Clinical Trials Registry (no. UMIN000027442) and the Japan Registry of Clinical Trials (no. jRCTs061180100).

The Switch/Sucrose Nonfermentable (SWI/SNF) complexes are chromatin remodeling factors that consist of multiple protein subunits. Each subunit plays a distinct role in gene regulation and is aberrantly expressed in tumors, such as neuroendocrine neoplasms (NENs). BRG1-associated factor 53B (BAF53B), which is also known as ACTL6B, is a neuron-specific subunit that acts as a regulator during neurogenesis. Because the BAF53B expression pattern in tumors is unknown, the present study investigated the expression in cell lines and tissues. Publicly available transcriptome data indicated that BAF53B mRNA was highly expressed in NEN-derived cell lines. We performed immunohistochemical staining on tissue microarrays of different types of NENs with neuroendocrine (NE) marker expression (n = 117) (small cell lung carcinoma (SCLC)lung carcinoid (LC), gastroenteropancreatic-NEN (GEP-NEN), esophageal neuroendocrine carcinoma (ENEC), medullary thyroid carcinoma (MTC), neuroblastoma (NB), and pheochromocytoma (PHEO)) and non-NENs (n = 178). While few positive cells were observed in many cases of non-NENs (e.g., lung adenocarcinoma), positive expression was found in cases of NENs (SCLC (14/19, 73.7%), LC (12/16, 75.0%), GEP-NEN (4/9, 44.4%), ENEC (1/2, 50.0%), MTC (24/27, 88.9%), NB (18/20, 90.0%), and PHEO (16/24, 66.7%)). In NCI-H889 cells, BAF53B knockdown did not affect the cellular viability, and its effect on NE marker expression was only marginal. However, a gene expression microarray analysis suggested that BAF53B-regulated genes were associated with the development and progression of NENs. Our analysis revealed that BAF53B was an immunohistochemical marker for specific NENs, indicating its potentially important role in the pathogenesis.