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Hepatocellular carcinoma (HCC) remains a global challenge due to high morbidity and mortality rates and poor response to treatment. Immunotherapy, based on introduction of dendritic cells (DCs) activated by tumor cell lysates as antigens ex vivo, shows limited response rates in HCC patients. Here, we demonstrate that tumor cell-derived exosomes (TEXs), displaying an array of HCC antigens, can elicit a stronger immune response than cell lysates in vitro and in vivo. Significant tumor growth inhibition was achieved in ectopic and orthotopic HCC mice treated with TEX-pulsed DCs. Importantly, the tumor immune microenvironment was significantly improved in orthotopic HCC mice treated by TEX-pulsed DCs, demonstrated by increased numbers of T lymphocytes, elevated levels of interferon-c, and decreased levels of interleukin-10 and tumor growth factor-b in tumor sites. As expected, T cells played an essential role in the TEX-pulsed DC-mediated immune response. Notably, exosomes from HCC cells not only promoted HCC-specific cytolysis but also provided cross-protective effects against pancreatic cancer cells. Moreover, HCC-specific cytolysis, elicited by DCs pulsed with human HepG2 cellderived exosomes, was observed across different human HCC cells irrespective of human leukocyte antigen types. Conclusion: HCC TEXs can potently carry HCC antigens, trigger a strong DC-mediated immune response, and improve the HCC tumor microenvironment. (HEPATOLOGY 2016;64:456-472) R anked as the sixth most lethal malignancy, hepatocellular carcinoma (HCC) attracts significant attention due to its aggressive nature, high mortality rate, and low response rates to treatments in the clinic.(1) Although surgical resection can extend the life span of HCC patients, it is only amenable to early-stage HCC patients and has a high recurrence rate that is far from ideal. Chemotherapeutic or radiotherapeutic interventions such as sorafenib, transcatheter arterial chemoembolization, and radiofrequency ablation are intensively used in the clinic; however, the survival benefit is limited.(2) Therefore, other interventional approaches have been rigorously pursued. Among these, dendritic cell (DC)-based immunotherapy is a promising strategy with clinical studies in humans. (3)(4)(5) The first-in-human clinical trial among HCC patients demonstrated proof-of-concept evidence for DC-based immunotherapy with HCC cell lysates as antigens; however, the response rate was marginal and the efficacy was low, (5) necessitating further investigation into other immunotherapy options.Recently, the discovery of physiological roles of the exosome, a nanovesicle secreted by cells, as an intercellular courier of protein, messenger RNA, and micro-RNA, has garnered considerable interest.(6) Exosomes have been extensively studied for diagnostic purposes

Advanced hepatocellular carcinoma (HCC) has limited therapeutic options. Immunotherapy is a promising treatment, while sorafenib is a first-line drug-based treatment for advanced HCC. However, the efficacy of sorafenib and immunotherapy in combination, have not been clearly evaluated. Sorafenib treatment has been shown to promote immunosuppression by increasing hypoxia in orthotopic HCC models. Here, we found that sorafenib treatment in mice with orthotopic HCC increased the expression of inhibitor programmed death-ligand 1 (PD-L1) and T-regulatory cells in tumor tissues. We pulsed dendritic cells with exosomes derived from tumor cells (DC-TEX) and found that the number of T-regulatory cells decreased and the number of CD8+T cells increased. However, combining DC-TEX and sorafenib did not prolong survival in these mice. Moreover, we found that the number of PD-1+CD8+T cells significantly increased after DC-TEX treatment. Therefore, we next added PD-1 antibody (PD-1 Ab) to the treatment regimen to block the PD-1/PD-L1 pathway, and found that the exhausted CD8+T cells were restored, without affecting the number of T-regulatory cells. Thus, our data suggest that the combination of DC-TEX and PD-1 Ab enhanced the efficacy of sorafenib, but treatment with either DC-TEX or PD-1 Ab alone, did not.

Our study demonstrated the presence of six differentially expressed serum microRNAs in HBV-positive small HCC compared to other benign liver diseases associated with HBV.

Triptolide is beneficial for the treatment of ulcerative colitis (UC), which is closely related to the gut microbiota. However, whether the therapeutic effects of triptolide involve the regulation of the gut microbiota is still unclear. In the present study, animal models of UC mice induced by dextran sodium sulfate (DSS) were established, the changes of gut microbiota in mice were detected by high-throughput sequencing. The effects of triptolide on DSS-induced UC mouse and its gut microbiota were studied. As a result, we found that triptolide exerted anti-inflammatory and therapeutic effects on UC mice. Sequencing results for the gut microbiota showed that the composition of the gut microbiota from DSS group was disordered as compared with that from the control group, consistent with a decrease in the abundance of flora. Triptolide treatment accelerated the recovery of the population of the gut microbiota and significantly improved the microbial diversity. At the phylum level, the population of Bacteroidetes decreased and that of Firmicutes increased. At the genus level, Bacteroides and Lachnospiraceae counts decreased. Thus, triptolide could regulate the composition of the gut microbiota, accelerate the recovery of microbiota, and exert good therapeutic effects in UC mice. Our results also revealed that fecal transplantation from triptolide-treated mice could relieve UC. This study provides a reference for the rational use of triptolide for the treatment of UC.

The aim of the current study was to identify biomarkers that correlate with the Barcelona Clinic Liver Cancer (BCLC) staging system and prognosis of patients with hepatocellular carcinoma (HCC). We downloaded 4 gene expression datasets from the Gene Expression Omnibus database (http://www.ncbi.nlm.nih.gov/geo), and screened for genes that were differentially expressed between HCC and normal liver tissues, using significance analysis of the microarray algorithm. We used a weighted gene co-expression network analysis (WGCNA) to identify hub genes that correlate with BCLC staging, functional enrichment analysis to associate hub genes with their functions, protein-protein interaction network analysis to identify interactions among hub genes, UALCAN analysis to assess gene expression levels based on tumour stage, and survival analyses to clarify the effects of hub genes on patients’ overall survival (OS). We identified 50 relevant hub genes using WGCNA; among them, 13 genes (including TIGD5, C8ORF33, NUDCD1, INSB8, and STIP1) correlated with OS and BCLC staging. Significantly enriched gene ontology biological process terms included RNA processing, non-coding RNA processing and phosphodiester bond hydrolysis, and 6 genes were found to interact with 10 or more hub genes. We identified several candidate biomarkers that correlate with BCLC staging and OS of HCC. These genes might be used for prognostic assessment and selection of HCC patients for surgery, especially those with intermediate or advanced disease.

Our findings demonstrate that micronodules can be specifically differentiated with high sensitivity from surrounding tissue with this molecule, opening clinical possibilities for early detection and precise surgery of HCC. (Hepatology 2018).

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