A5025405931- Cancer Immunotherapy and Biomarkers
- Fibroblast Growth Factor Research
- Pancreatic and Hepatic Oncology Research
- Immune Cell Function and Interaction
- Cancer, Hypoxia, and Metabolism
- Immune cells in cancer
- Liver physiology and pathology
- GDF15 and Related Biomarkers
- Liver Disease Diagnosis and Treatment
- Hepatocellular Carcinoma Treatment and Prognosis
- Immunotherapy and Immune Responses
- Kruppel-like factors research
- CAR-T cell therapy research
- Cholangiocarcinoma and Gallbladder Cancer Studies
- Nutrition and Health in Aging
- Cancer Research and Treatments
- Macrophage Migration Inhibitory Factor
- Vagus Nerve Stimulation Research
- T-cell and B-cell Immunology
- Nuclear Receptors and Signaling
- Adenosine and Purinergic Signaling
- Phagocytosis and Immune Regulation
- Peptidase Inhibition and Analysis
- Cancer Mechanisms and Therapy
- Single-cell and spatial transcriptomics
National Cancer Institute
2022-2025
National Institutes of Health
2022-2025
Center for Cancer Research
2022-2025
Osaka University
2017-2024
ORCID
2022
Background Oncolytic immunotherapy represents a unique therapeutic platform for the treatment of cancer. Here, we evaluated safety and efficacy combination pexastimogene devacirepvec (PexaVec) plus durvalumab (anti-programmed death ligand 1) with without tremelimumab (anti-cytotoxic T-lymphocyte associated protein 4) in patients standard chemotherapy refractory mismatch repair proficient (pMMR) metastatic colorectal cancer (mCRC) phase I/II trial. Methods Adult histologically confirmed...
Background & AimsAlthough the tumor microenvironment plays an important role in growth, it is not fully understood what hepatic stellate cells (HSCs) play hepatocellular carcinoma (HCC) microenvironment.MethodsA high-fat diet after streptozotocin was administered to HSC-specific Atg7-deficient (GFAP-Atg7 knockout [KO]) or growth differentiation factor 15 (GDF15)-deficient (GFAP-GDF15KO) mice. LX-2 cells, a human HSC cell line, were cultured with hepatoma cells.ResultsIn steatohepatitis-based...
Atezolizumab/bevacizumab (Atezo/Bev) combination therapy has become a front-line for advanced hepatocellular carcinoma (HCC), but approximately 20% of patients are nonresponders. We investigated circulating biomarkers to predict therapeutic outcomes. performed simultaneous measurement 34 proteins using multiplex bead-based immunoassay in baseline plasma from who underwent Atezo/Bev as first- or second-line treatment. Logistic regression analysis showed that IL-6 and interferon alpha (IFNα)...
Combination immunotherapy with anti-programmed cell death1-ligand1 (PD-L1) and anti-vascular endothelial growth factor (VEGF) antibodies has become the standard treatment for patients unresectable HCC (u-HCC). However, limited obtain clinical benefits. Cell-free DNA (cfDNA) in peripheral blood contains circulating tumor (ctDNA) that reflects molecular abnormalities tissue. We investigated potential of cfDNA/ctDNA as biomarkers predicting therapeutic outcome u-HCC treated anti-PD-L1/VEGF...
Background Microsatellite stable colorectal liver metastases (MSS CLM) maintain an immunosuppressive tumor microenvironment (TME). Historically, immune-based approaches have been ineffective. VB-111 (ofranergene obadenovec) is a genetically-modified adenoviral vector targeting the TME; its unique dual mechanism induces immune response and disrupts neovascularization. Checkpoint inhibition may synergize induced by viral-mediated anti-angiogenic gene therapy. We aimed to examine safety...
Background Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality. The combination tremelimumab and durvalumab now standard treatment option for advanced HCC. Objective To study immune responses in HCC patients treated with durvalumab. Design We 28 durvalumab, locoregional therapies. performed high-dimensional multiomics analysis including whole exome sequencing, single-cell RNA seq, CO-Detection by indEXing, flow cytometry multiplex cytokine/chemokine patients’ blood...
Inbred mouse strains are critical tools for studying immune regulation of metabolic dysfunction-associated steatohepatitis (MASH) and hepatocellular carcinoma (HCC). Here, we profiled strain-associated hepatic differences, performed mice-human cross-species comparisons. Immune landscapes C57BL/6, BALB/c, FVB/N mice were compared under healthy, MASH, or HCC state using high-dimensional spectral flow cytometry (n = 4 per condition). MASH was induced by feeding methionine- choline-deficient...
Abstract Purpose: Hepatocellular carcinoma (HCC) is characterized by high intertumor heterogeneity of genetic drivers. Two multitarget tyrosine kinase inhibitors (TKI), lenvatinib and sorafenib, are used as standard-of-care chemotherapeutics in patients with advanced HCC, but a stratification strategy has not been established because lack efficacious biomarkers. Therefore, we sought biomarkers that indicate lenvatinib-susceptible HCC. Experimental Design: We performed screening HCC driver...
Abstract Background Current standard of care for advanced biliary tract cancer (BTC) is gemcitabine, cisplatin plus anti‐PD1/PD‐L1, but response rates are modest. The purpose this study was to explore the efficacy and safety durvalumab (anti‐PD‐L1) tremelimumab (anti‐CTLA‐4), with without an interventional radiology (IR) procedure in BTC. Methods Eligible patients BTC who had received or refused at least one prior line systemic therapy were treated four combined doses followed by monthly...
Abstract Liver cancer ranks amongst the deadliest cancers. Nerves have emerged as an understudied regulator of tumor progression. The parasympathetic vagus nerve influences systemic immunity via acetylcholine (ACh). Whether cholinergic neuroimmune interactions influence hepatocellular carcinoma (HCC) remains uncertain. denervation hepatic vagotomy (HV) significantly reduced liver burden, while pharmacological enhancement tone promoted growth. Cholinergic disruption in Rag1KO mice revealed...
Background: There is a need for novel noninvasive markers metabolic dysfunction–associated steatotic liver disease (MASLD) to stratify patients at high risk liver-related events including cancer and decompensation. In the present study, we used proteomic analysis of proteins in extracellular vesicles (EVs) identify new biomarkers that change with fibrosis progression can predict development events. Methods: We analyzed serum EVs from 50 MASLD assessed by biopsy identified altered advanced...
Background & AimsAlthough nonalcoholic fatty liver disease (NAFLD) is closely associated with obesity, the role of adipose tissue in NAFLD not well-understood. Because autophagy has been reported to be involved degradation lipid droplets, we investigated pathogenesis NAFLD.MethodsC57BL/6J mice and adipocyte-specific Atg7-knockout (Adipoq-Atg7 KO mice) were fed a high-fat diet (HFD).ResultsHFD feeding for up 4 months increased both inguinal epididymal white (iWAT eWAT, respectively; former...
Regorafenib is used for hepatocellular carcinoma (HCC), but its response does not last long, partly due to chemoresistance acquisition. We performed a clustered regularly interspaced short palindromic repeats (CRISPR)-based loss-of-function genetic screen and aimed discover molecules involved in regorafenib resistance HCC. Xenograft tumors established from Cas9-expressing HCC cells with pooled CRISPR kinome libraries were treated or vehicle. Sequencing analysis identified 31 genes, the...
We evaluated the value of secreted glycoprotein thrombospondin-2 (TSP-2) to predict hepatocellular carcinoma (HCC) occurrence in chronic hepatitis C (CHC) patients after Hepatitis virus (HCV) elimination by direct-acting antiviral agents (DAAs). A total 786 CHC without an HCC history who achieved a sustained virological response (SVR) with DAAs were randomly assigned 2:1, 524 as derivation cohort and 262 validation cohort. Serum TSP-2 levels at end treatment measured enzyme-linked...
Summary Background and Aims Although metabolic dysfunction‐associated steatotic liver disease (MASLD) patients with a Fib‐4 index >1.3 are recommended for fibrosis evaluation via elastography or biopsy, more convenient method identifying high‐risk populations requiring follow‐up is needed. We explored the utility of serum levels growth differentiation factor‐15 (GDF15), cell stress‐responsive cytokine related to syndrome, stratifying risk clinical events in MASLD patients. Methods Serum...
Diabetes mellitus is a well-known risk factor for pancreatic cancer. We focused on hyperglycemia, main feature of diabetes mellitus, and uncovered its effect precancerous intraepithelial neoplasia (PanIN) progression. In vivo induction hyperglycemia with 100 mg/kg streptozotocin in KrasLSL G12D Pdx1Cre (KP) mice promoted the PanIN formation Preconditioning high- or low-glucose medium 28 days showed that high-glucose environment increased cell viability sphere PANC-1, Kras-mutant human ductal...
Summary Background After hepatitis C virus (HCV) elimination, patients should be followed up due to risk of hepatocellular carcinoma (HCC). Growth differentiation factor 15 (GDF15) is a cytokine induced by mitochondrial dysfunction or oxidative stress. Aim To evaluate the prognostic value GDF15 for HCC occurrence after HCV elimination. Methods We measured levels in stored serum from with chronic infection without history who had achieved sustained virological response direct‐acting antiviral...
Objective Liver metastases are often resistant to immune checkpoint inhibitor therapy (ICI) and portend a worse prognosis compared with other locations. Regulatory T cells (Tregs) one of several immunosuppressive implicated in ICI resistance liver tumours, but the role played by Tregs residing within surrounding tumour is unknown. Design Flow cytometry single-cell RNA sequencing were used characterise hepatic before after therapy. Results We found that murine houses Treg population that,...
The efficacy of immune checkpoint inhibitor (ICI) therapy for liver cancer remains limited. As the hypoxic environment regulates adenosine signaling, we tested A2a receptor (A2aR) inhibition in combination with ICI treatment murine models cancer.
Abstract The gut microbiome and liver are anatomically functionally connected. impact of the microbiota or microbial metabolites on cancer progression via immune cells has been recently revealed across various preclinical models. Commensal microbes patients differ from control subjects, their composition is affected by etiology hepatocellular carcinoma. represents a potential novel target for intervention as shown in with melanoma, but we still lack data Fecal transplantation dietary...
Innate lymphoid cells (ILC) are a heterogeneous and plastic population of the innate immune system. Their role in cancer specifically hepatocellular carcinoma is unraveling. The presence ILCs peripheral blood HCC patients has not been explored yet. function response to checkpoint inhibitor therapy have also explored. Here, we characterized PBMC at baseline after treatment with inhibitors (ICI) by flow cytometry single-cell sequencing. Characterization ILC subsets PBMCs showed significant...
Abstract Cancer cachexia, a paraneoplastic syndrome characterized by ongoing skeletal muscle mass loss, is accompanied adipose tissue loss and strongly affects chemotherapy endurance. Our aim was to detect serum marker reflecting pancreatic cancer cachexia predicting subsequent of tissue, focusing on tissue‐secreted proteins. Murine‐derived cells were orthotopically injected into the mouse tail. After 3 weeks, RNA sequencing perigonadal fat orthotopic tumors carried out. We analyzed stocked...