• ANTIGENS
• HEPATOCELLULAR CARCINOMA
• IMMUNOTHERAPY
• T LYMPHOCYTES
• T-CELL RECEPTOR

• drug delivery system
• nanoparticles
• tumor marker detection
• tumor therapy

• Humans
• Liver Neoplasms/therapy
• Liver Neoplasms/diagnosis
• Carcinoma, Hepatocellular/therapy
• Carcinoma, Hepatocellular/diagnosis
• Photochemotherapy/methods
• Animals
• Nanotechnology/methods
• Biomarkers, Tumor
• Metal Nanoparticles/chemistry
• Antineoplastic Agents/administration & dosage
• Antineoplastic Agents/therapeutic use
• Drug Delivery Systems/methods

• HCC
• Immunotherapy
• Liver Cancer
• Stem cells

• Humans
• Liver Neoplasms/therapy
• Liver Neoplasms/immunology
• Immunotherapy/methods
• Animals
• Carcinoma, Hepatocellular/therapy
• Carcinoma, Hepatocellular/immunology
• Stem Cell Transplantation

• Capmatinib
• Hepatocellular carcinoma
• MET
• Spartalizumab
• anti-programmed death-ligand 1

• Liver cancer
• bibliometric analysis
• immunotherapy
• oncology
• research trends

• Humans
• Liver Neoplasms/therapy
• Bibliometrics
• Immunotherapy/methods
• Tumor Microenvironment
• Biomedical Research

• Codonopsis pilosula glucofructan
• antitumor immune response
• apoptosis mechanisms

• Animals
• Mice
• Codonopsis
• Interferon-gamma
• Fructans
• Neoplasms/drug therapy
• Immunity, Cellular

• Cell culture
• Hepatocellular carcinoma (HCC)
• Lab-on-a-chip
• Metabolomics
• Microfluidic NMR

• Humans
• Carcinoma, Hepatocellular/metabolism
• Carcinoma, Hepatocellular/pathology
• Liver Neoplasms/metabolism
• Liver Neoplasms/pathology
• Microfluidics
• Cell Culture Techniques
• Magnetic Resonance Spectroscopy
• Metabolomics/methods
• Tumor Microenvironment

• 26813 Cancer Research UK
• MR/S009388/1 Medical Research Council

Immune checkpoint inhibitors are a class of anti-cancer therapy that work by harnessing the body’s immune system to promote cancer cell death. These drugs have become standard of care for many types of cancer, including melanoma and lung cancer, after clinical trials showed they work better than traditional chemotherapy. The role of immune checkpoint inhibitors is still evolving in the treatment of cancers of the gastrointestinal tract. This article examines the literature to support the use of immune checkpoint inhibitors to treat cancers of each part of the gastrointestinal system.

Gastrointestinal (GI) malignancies are a heterogenous group of cancers with varying epidemiology, histology, disease course, prognosis and treatment options. Immune checkpoint inhibitors (ICIs) have changed the landscape of modern cancer treatment, though they have demonstrated survival benefit in other solid tumors more readily than in GI malignancies. This review article presents an overview of the landscape of ICI use in GI malignancies and highlights recent updates in this rapidly evolving field.

• CyTOF
• Hepatocellular carcinoma
• TACE
• Tumor microenvironment
• Tumor necrosis

• liver hepatocellular carcinoma
• lrp1b mutation
• prognosis
• tumor mutation burden

• Biomarkers, Tumor/genetics
• Carcinoma, Hepatocellular/genetics
• Carcinoma, Hepatocellular/pathology
• Humans
• Liver Neoplasms/genetics
• Liver Neoplasms/pathology
• Mutation
• Prognosis
• Receptors, LDL/genetics

• Clinical trials
• Hepatocellular carcinoma
• Immune checkpoint inhibitors
• Immunotherapy
• Liver cancer
• Real-world data

• Anti-tumor immunity
• GO-PEI-PEG
• HCC ferroptosis
• PD-L1 siRNA

• Animals
• B7-H1 Antigen/genetics
• Carcinoma, Hepatocellular/drug therapy
• Ferroptosis
• Graphite
• Liver Neoplasms/drug therapy
• Mice
• Mice, Inbred C57BL
• Programmed Cell Death 1 Receptor
• RNA, Small Interfering/genetics
• Sorafenib/pharmacology

• Animals
• Antineoplastic Agents/chemical synthesis
• Antineoplastic Agents/therapeutic use
• Calreticulin/metabolism
• Carcinoma, Hepatocellular/drug therapy
• Cell Line, Tumor
• Cell Proliferation/drug effects
• Coordination Complexes/chemical synthesis
• Coordination Complexes/therapeutic use
• Dendritic Cells/metabolism
• Endoplasmic Reticulum Stress/drug effects
• Humans
• Imidazoles/chemical synthesis
• Imidazoles/therapeutic use
• Immunity/drug effects
• Immunogenic Cell Death/drug effects
• Liver Neoplasms/drug therapy
• Male
• Mice, Inbred C57BL
• Platinum/chemistry
• Reactive Oxygen Species/metabolism
• T-Lymphocytes/metabolism
• Mice

Hepatocellular carcinoma remains one of the leading causes of death from cancer worldwide as most cases are diagnosed at an advanced disease stage. Ramucirumab, a human anti-VEGFR-2 monoclonal antibody, is approved as a monotherapy for the treatment of patients with hepatocellular carcinoma and α-fetoprotein levels ≥400 ng/mL previously treated with sorafenib. As most patients present with an advanced disease, patients with α-fetoprotein levels ≥400 ng/mL have an aggressive disease and a poor prognosis, making ramucirumab an important treatment option for this subgroup of patients. This article provides a comprehensive review of the clinical efficacy of ramucirumab as highlighted in the two major trials that lead to its approval. We also briefly review the agent pharmacologic properties, as well as its safety and toxicity profile, before discussing certain limitations and challenges associated with ramucirumab use. Finally, we review completed and ongoing clinical trials and focus on those involving ramucirumab-based combinations, namely with immune therapy.

• hepatocellular carcinoma
• ramucirumab
• targeted therapy

• atezolizumab
• hepatocellular carcinoma
• second-line
• sorafenib

• PD-1
• hepatocellular carcinoma
• immunotherapy
• metastases
• pulmonary

Embryonic development and tumorigenesis have a certain degree of similarity. Alpha-fetoprotein (AFP), a protein related to embryonic development, is a well-known biomarker for the diagnosis and prognosis of hepatocellular carcinoma (HCC). In this study, we analyzed the differences in gene expression profiles and molecular mechanisms in human HCC tissues from patients in AFP^high (serum AFP level ≥ 25 ng/mL) and AFP^low (serum AFP level < 25 ng/mL) groups. The results indicated that AFP^high HCC has more malignant biological characteristics. Single-sample gene set enrichment analysis (ssGSEA) showed significantly higher levels of genes expressed in dendritic cells, neutrophils, and natural killer cells in the AFP^low group than in the AFP^high group. Then, we defined a rhesus monkey fetal liver developmental landscape and compared it to the HCC gene expression profile. The gene signatures of AFP^high HCC tissues were similar to those of early embryonic liver tissues. In this study, we comprehensively analyzed the rhesus monkey liver transcriptome during development and human primary HCC AFP-related gene expression profiles and clarified the function of AFP in the occurrence and development of HCC from the perspective of developmental biology, which might provide a new perspective on the pathogenesis of HCC.

• AFP
• embryonic liver development
• hepatocellular carcinoma
• rhesus monkey
• tumor immunity

• Immunosuppression
• Low molecular weight chitosan
• Thymopentin

Ginsenoside Rk1 and Rg5 are minor ginseng saponins that have received more attention recently because of their high oral bioavailability. Each of them can effectively inhibit the survival and proliferation of human liver cancer cells, but the underlying mechanism remains largely unknown. Network pharmacology and bioinformatics analysis demonstrated that G-Rk1 and G-Rg5 yielded 142 potential targets, and shared 44 putative targets associated with hepatocellular carcinoma. Enrichment analysis of the overlapped genes showed that G-Rk1 and G-Rg5 may induce apoptosis of liver cancer cells through inhibition of mitogen-activated protein kinase (MAPK) and nuclear factor-kappa B (NF-κB) signal pathways. Methyl thiazolyl tetrazolium (MTT) assay was used to confirm the inhibition of cell viability with G-Rk1 or G-Rg5 in highly metastatic human cancer MHCC-97H cells. We evaluated the apoptosis of MHCC-97H cells by using flow cytometry and 4′,6-diamidino-2-phenylindole (DAPI) staining. The translocation of Bax/Bak led to the depolarization of mitochondrial membrane potential and release of cytochrome c and Smac. A sequential activation of caspase-9 and caspase-3 and the cleavage of poly(ADP-ribose) polymerase (PARP) were observed after that. The levels of anti-apoptotic proteins were decreased after treatment of G-Rk1 or G-Rg5 in MHCC-97H cells. Taken together, G-Rk1 and G-Rg5 promoted the endogenous apoptotic pathway in MHCC-97H cells by targeting and regulating some critical liver cancer related genes that are involved in the signal pathways associated with cell survival and proliferation.

• bioinformatics analysis
• cytotoxicity
• endogenous apoptotic pathway
• ginsenoside
• human liver cancer
• network pharmacology

• Antineoplastic Agents, Phytogenic/chemistry
• Antineoplastic Agents, Phytogenic/pharmacology
• Carcinoma, Hepatocellular/drug therapy
• Carcinoma, Hepatocellular/metabolism
• Cell Line, Tumor
• Cell Proliferation/drug effects
• Cell Survival/drug effects
• Gene Expression Regulation, Neoplastic/drug effects
• Ginsenosides/chemistry
• Ginsenosides/pharmacology
• Humans
• Liver Neoplasms/drug therapy
• Liver Neoplasms/metabolism
• Mitogen-Activated Protein Kinases/metabolism
• NF-kappa B/metabolism
• Signal Transduction/drug effects

• Biomarker
• Hepatocellular carcinoma
• Immune
• Prognostic

• Biomarkers, Tumor/metabolism
• Carcinoma, Hepatocellular/immunology
• Carcinoma, Hepatocellular/mortality
• Carcinoma, Hepatocellular/pathology
• Humans
• Liver Neoplasms/immunology
• Liver Neoplasms/mortality
• Liver Neoplasms/pathology
• Prognosis
• Survival Analysis
• Tumor Microenvironment/immunology

• YCZYPT[2018]06 the Cancer Genome Atlas of China (CGAC) project from the National Human Genetic Resources Sharing Service Platform (2005DKA21300)
• XDB38040100 the Strategic Priority Research Program of the Chinese Academy of Sciences, China

Hepatocellular carcinoma (HCC) arises in the setting of advanced liver fibrosis, a dynamic and complex inflammatory disease. The tumor microenvironment (TME) is a mixture of cellular components including cancer cells, cancer stem cells (CSCs), tumor-associated macrophages (TAM), and dendritic cells (DCs), which might drive to tumor progression and resistance to therapies. In this work, we study the effects of 4-methylumbelliferone (4Mu) on TME and how this change could be exploited to promote a potent immune response against HCC. First, we observed that 4Mu therapy induced a switch of hepatic macrophages (Mϕ) towards an M1 type profile, and HCC cells (Hepa129 cells) exposed to conditioned medium (CM) derived from Mϕ treated with 4Mu showed reduced expression of several CSCs markers and aggressiveness. HCC cells incubated with CM derived from Mϕ treated with 4Mu grew in immunosuppressed mice while presented delayed tumor progression in immunocompetent mice. HCC cells treated with 4Mu were more susceptible to phagocytosis by DCs, and when DCs were pulsed with HCC cells previously treated with 4Mu displayed a potent antitumoral effect in therapeutic vaccination protocols. In conclusion, 4Mu has the ability to modulate TME into a less hostile milieu and to potentiate immunotherapeutic strategies against HCC.

Chronic hepatitis C virus (cHCV) infection is a major global health burden and the leading cause of hepatocellular carcinoma (HCC) in the Western world. The course and outcome of HCV infection is centrally influenced by CD8⁺ T cell responses. Indeed, strong virus-specific CD8⁺ T cell responses are associated with spontaneous viral clearance while failure of these responses, e.g., caused by viral escape and T cell exhaustion, is associated with the development of chronic infection. Recently, heterogeneity within the exhausted HCV-specific CD8⁺ T cells has been observed with implications for immunotherapeutic approaches also for other diseases. In HCC, the presence of tumor-infiltrating and peripheral CD8⁺ T cell responses correlates with a favorable prognosis. Thus, tumor-associated and tumor-specific CD8⁺ T cells are considered suitable targets for immunotherapeutic strategies. Here, we review the current knowledge of CD8+ T cell responses in chronic HCV infection and HCC and their respective failure with the potential consequences for T cell-associated immunotherapeutic approaches.

• CD8+ T cells
• HCC
• HCV
• T cell exhaustion
• checkpoint blockade therapy

• HCC
• LncRNA
• biomarkers
• therapeutic and diagnostic targets

Minimally invasive radiofrequency ablation (RFA) is used as a first-line treatment option for hepatocellular cancer (HCC) with the weaknesses of incomplete ablation, tumor recurrence, and inferior outcomes. To overcome this limitation, we proposed to develop sunitinib-RFA integrated therapy with a potential of activating anti-HCC immune response.

Using our unique murine model, we developed a novel RFA platform with a modified human cardiac RF generator. Therapeutic efficacy of sunitinib–RFA combined treatment in HCC was tested in this platform. Tumor progression was monitored by MRI; tumor necrosis and apoptosis were detected by H&E and terminal deoxynucleotidyl transferase dUTP nick end labeling; immune reaction was defined by flow cytometry; and signaling molecules were examined with real-time PCR (qPCR), western blot, and immunohistochemical staining.

A significantly reduced tumor growth and extended lift span were observed in the mice receiving combined treatment with RFA and sunitinib. This combined treatment significantly increased the frequency of CD8⁺ T cell, memory CD8⁺ T cell, and dendritic cells (DCs); decreased the frequency of regulatory T cells; and activated tumor-specific antigen (TSA) immune response in tumor microenvironment. We found that RFA caused PD-1 upregulation in tumor-infiltrated T cells by boosting hepatocyte growth factor (HGF) expression, which was suppressed by sunitinib treatment. We have also demonstrated that sunitinib suppressed VEGF’s effect in enhancing PD-L1 expression in DCs and attenuated heat-sink effect. The results indicate that RFA induced tumor destruction and release of in situ TSAs which can activate a tumoricidal immune response in sunitinib-treated mice, significantly improving anti-HCC therapeutic efficacy.

Sunitinib enables RFA-released in situ TSA to ignite an effective anti-tumor immune response by suppressing HGF and VEGF signaling pathways. Sunitinib–RFA as a synergistic therapeutic approach significantly suppresses HCC growth.

• combined modality therapy
• immune tolerance
• immunomodulation
• liver neoplasms
• lymphocytes
• tumor-infiltrating

• Animals
• Carcinoma, Hepatocellular/radiotherapy
• Dendritic Cells/metabolism
• Disease Models, Animal
• Humans
• Immunity/immunology
• Liver Neoplasms/radiotherapy
• Mice
• Radiofrequency Ablation/methods
• Sunitinib/pharmacology
• Sunitinib/therapeutic use

• I01 BX004065 BLRD VA
• R01 CA208396 NCI NIH HHS
• VA merit Award I01
• Foundation for the National Institutes of Health

There is no established postoperative adjuvant therapy for hepatocellular carcinoma (HCC), and improvement of patient prognosis has been limited. We conducted long‐term monitoring of patients within a phase II trial that targeted a cancer antigen, glypican‐3 (GPC3), specifically expressed in HCC. We sought to determine if the GPC3 peptide vaccine was an effective adjuvant therapy by monitoring disease‐free survival and overall survival. We also tracked GPC3 immunohistochemical (IHC) staining, CTL induction, and postoperative plasma GPC3 for a patient group that was administered the vaccine (n = 35) and an unvaccinated patient group that underwent surgery only (n = 33). The 1‐y recurrence rate after surgery was reduced by approximately 15%, and the 5‐y and 8‐y survival rates were improved by approximately 10% and 30%, respectively, in the vaccinated group compared with the unvaccinated group. Patients who were positive for GPC3 IHC staining were more likely to have induced CTLs, and 60% survived beyond 5 y. Vaccine efficacy had a positive relationship with plasma concentration of GPC3; high concentrations increased the 5‐y survival rate to 75%. We thus expect GPC3 vaccination in patients with HCC, who are positive for GPC3 IHC staining and/or plasma GPC3 to induce CTL and have significantly improved long‐term prognosis.

• cytotoxic T lymphocyte
• glypican-3
• hepatocellular carcinoma
• immunohistochemical staining
• peptide vaccine

• Immunomodulation
• check point inhibitors
• hepatocellular carcinoma
• radiofrequency

A majority of hepatocellular carcinoma (HCC) develops in the setting of persistent chronic inflammation as immunological mechanisms have been shown to play a vital role in the initiation, growth and progression of tumours. The index review has been intended to highlight ongoing immunological changes in the hepatic parenchyma responsible for the genesis and progression of HCC. The in-situ vaccine effect of radiofrequency (RF) is through generation tumour-associated antigens (TAAs), following necrosis and apoptosis of tumour cells, which not only re-activates the antitumour immune response but can also act in synergism with checkpoint inhibitors to generate a superlative effect with intent to treat primary cancer and distant metastasis. An improved understanding of oncogenic responses of immune cells and their integration into signaling pathways of the tumour microenvironment will help in modulating the antitumour immune response. Finally, we analyzed contemporary literature and summarised the recent advances made in the field of targeted immunotherapy involving checkpoint inhibitors along with RF application with the intent to reinstate antitumour immunity and outline future directives in very early and early stages of HCC.

• carcinoma
• checkpoint inhibitors
• hepatocellular
• immunomodulation
• radiofrequency

Immunotherapy represents a promising option for treatment of hepatocellular carcinoma (HCC) in cirrhotic patients but its efficacy is currently inconsistent and unpredictable. Locoregional therapies inducing immunogenic cell death, such as transarterial chemoembolization (TACE) or selective internal radiation therapy (SIRT), have the potential to act synergistically with immunotherapy. For the development of new approaches combining locoregional treatments with immunotherapy, a better understanding of the respective effects of TACE and SIRT on recruitment and activation of immune cells in HCC is needed. To address this question, we compared intra-tumor immune infiltrates in resected HCC after preoperative treatment with TACE or SIRT.

Data fromr patients undergoing partial hepatectomy for HCC, without preoperative treatment (SURG, n = 32), after preoperative TACE (TACE, n = 16), or preoperative SIRT (n = 12) were analyzed. Clinicopathological factors, tumor-infiltrating lymphocytes (TILs), CD4⁺ and CD8⁺ T cells, and granzyme B (GZB) expression in resected HCC, and postoperative overall and progression-free survival were compared between the three groups.

Clinicopathological and surgical characteristics were similar in the three groups. A significant increase in TILs, CD4⁺ and CD8⁺ T cells, and GZB expression was observed in resected HCC in SIRT as compared to TACE and SURG groups. No difference in immune infiltrates was observed between TACE and SURG patients. Within the SIRT group, the dose of irradiation affected the type of immune infiltrate. A significantly higher ratio of CD3⁺ cells was observed in the peri-tumoral area in patients receiving < 100 Gy, whereas a higher ratio of intra-tumoral CD4⁺ cells was observed in patients receiving > 100 Gy. Postoperative outcomes were similar in all groups. Irrespective of the preoperative treatment, the type and extent of immune infiltrates did not influence postoperative survival.

SIRT significantly promotes recruitment/activation of intra-tumor effector-type immune cells compared to TACE or no preoperative treatment. These results suggest that SIRT is a better candidate than TACE to be combined with immunotherapy for treatment of HCC. Evaluation of the optimal doses for SIRT for producing an immunogenic effect and the type of immunotherapy to be used require further evaluation in prospective studies.

• Hepatocellular carcinoma
• Immunotherapy
• Locoregional therapy
• Selective internal radiation therapy (SIRT)
• Transarterial chemoembolization (TACE)
• Tumor-infiltrating lymphocytes

Metastasis and metabolism reprogramming are two major hallmarks of cancer. In the initiation and progression of cancer, tumor cells are known to undergo fundamental metabolic changes to sustain their development and progression. In recent years, much more attentions have been drawn to their important roles in facilitating cancer metastasis through regulating the biological properties. In this review, we summarized the recent progresses in the studies of metabolism reprogramming of cancer metastasis, particularly of primary liver cancer, and highlight their potential applications.

• Amino acid
• Cancer metastasis
• Cholesterol
• Fatty acid
• Glucose
• Primary liver cancer
• Tumor microenvironment

Background & Aims: In hepatocellular carcinoma (HCC), CD8+ T-cell responses targeting tumor-associated antigens (TAA) are considered to be beneficial. However, the molecular profile of TAA-specific CD8+ T cells in HCC is not well defined due to their low frequency.

Results: In this study, we demonstrate that TAA-specific CD8+ T-cell responses are not efficiently induced in the peripheral blood of HCC patients as supported by the following observations: First, in HCC patients, frequencies of TAA-specific CD8+ T cells were not increased compared to healthy donors (HD) or patients with liver cirrhosis. Second, a remarkable proportion of TAA-specific CD8+ T cells were naïve despite the presence of antigen within the tumor tissue. Third, antigen-experienced TAA-specific CD8+ T cells lack the characteristic transcriptional regulation of exhausted CD8+ T cells, namely Eomes^hiTbet^dim, and express inhibitory receptors only on a minor proportion of cells. This suggests restricted antigen recognition and further supports the hypothesis of inefficient induction and activation.

Methods: By applying peptide/MHCI tetramer-based enrichment, a method of high sensitivity, we now could define the heterogeneity of circulating TAA-specific CD8+ T cells targeting glypican-3, NY-ESO-1, MAGE-A1 and MAGE-A3. We focused on therapy-naïve HCC patients of which the majority underwent transarterial chemoembolization (TACE).

Conclusion: Our analysis reveals that circulating TAA-specific CD8+ T cells targeting 4 different immunodominant epitopes are not properly induced in therapy-naïve HCC patients thereby unravelling new and unexpected insights into TAA-specific CD8+ T-cell biology in HCC. This clearly highlights severe limitations of these potentially anti-tumoral T cells that may hamper their biological and clinical relevance in HCC.

• HCC
• MAGE-A
• T-cell exhaustion
• TAA
• liver cirrhosis

• biomarker
• cancer-testis antigen
• hepatocellular carcinoma
• immunotherapy

This case report describes the abscopal resolution of a liver metastasis in a patient with two separate primary malignancies. A 70-year-old male with an unresectable cholangiocarcinoma with an associated 5 cm liver metastasis was found during his staging investigations to have a 1.8 cm right upper lobe lung tumor. A CT-guided biopsy of the lung tumor revealed a primary adenocarcinoma of lung origin. Given the expected worse prognosis of the metastatic cholangiocarcinoma, after review of his case in provincial gastrointestinal and lung tumor boards, he was treated with eight cycles of palliative gemcitabine and cisplatin chemotherapy. Post eight cycles, the disease in the liver and the lung was stable. After completion of first line palliative systemic therapy, radical stereotactic body radiotherapy (SBRT), consisting of 48 Gy in four fractions, was delivered to the right upper lobe non-small cell lung cancer (NSCLC) primary. Three months post-completion of the SBRT, restaging CT scans were performed which revealed the intriguing spontaneous and complete resolution of his liver metastasis. These findings were confirmed on subsequent MRI imaging of his liver. As his liver metastasis was well outside of the SBRT fields, the spontaneous resolution of his liver metastasis presents clinical evidence of the abscopal effect of cholangiocarcinoma in response to SBRT to his lung tumor.

• abscopal effect
• cholangiocarcinoma
• liver metastasis
• non-small cell lung cancer
• stereotactic radiotherapy

• Hepatocellular carcinoma (HCC)
• immune checkpoint
• immunotherapy
• natural killer cell (NK cell)

Dendritic cell (DC)-derived exosomes (Dexs) have been proved to induce and enhance antigen-specific T cell responses in vivo, and previous clinical trials have shown the feasibility and safety of Dexs in multiple human cancers. However, there is little knowledge on the efficacy of Dexs against hepatocellular carcinoma (HCC) until now.

In this study, human peripheral blood-derived DCs were loaded with recombinant adeno-associated viral vector (rAAV)-carrying alpha-fetoprotein (AFP) gene (rAAV/AFP), and high-purity Dexs were generated. Then naive T cells were stimulated with Dexs to investigate the specific T cell-mediated immune responses against HCC.

Our findings showed that Dexs were effective to stimulate naive T cell proliferation and induce T cell activation to become antigen-specific cytotoxic T lymphocytes (CTLs), thereby exhibiting antitumor immune responses against HCC. In addition, Dex-sensitized DC precursors seemed more effective to trigger major histocompatibility complex class I (MHC I)-restricted CTL response and allow DCs to make full use of the minor antigen peptides, thereby maximally activating specific immune responses against HCC.

It is concluded that Dexs, which combine the advantages of DCs and cell-free vectors, are promising to completely, or at least in part, replace mature DCs (mDCs) to function as cancer vaccines or natural antitumor adjuvant.

• cytotoxic T lymphocyte
• dendritic cell
• exosome
• hepatocellular carcinoma
• immune response

• HCC Model
• Immune Regulation
• Liver Cancer
• Nanotechnology
• Tumor Microenvironment

Hepatocellular carcinoma (HCC) has become a leading cause of cancer-related death, making the elucidation of its underlying mechanisms an urgent priority. Inflammation is an adaptive response to infection and tissue injury under strict regulations. When the host regulatory machine runs out of control, nonresolving inflammation occurs. Nonresolving inflammation is a recognized hallmark of cancer that substantially contributes to the development and progression of HCC. The HCC-associated inflammation can be initiated and propagated by extrinsic pathways through activation of pattern-recognition receptors (PRRs) by pathogen-associated molecule patterns (PAMPs) derived from gut microflora or damage-associated molecule patterns (DAMPs) released from dying liver cells. The inflammation can also be orchestrated by the tumor itself through secreting factors that recruit inflammatory cells to the tumor favoring the buildup of a microenvironment. Accumulating datas from human and mouse models showed that inflammation promotes HCC development by promoting proliferative and survival signaling, inducing angiogenesis, evading immune surveillance, supporting cancer stem cells, activating invasion and metastasis as well as inducing genomic instability. Targeting inflammation may represent a promising avenue for the HCC treatment. Some inhibitors targeting inflammatory pathways have been developed and under different stages of clinical trials, and one (sorafenib) have been approved by FDA. However, as most of the data were obtained from animal models, and there is a big difference between human HCC and mouse HCC models, it is challenging on successful translation from bench to bedside.

• LY2109761
• hepatocellular carcinoma ( HCC)
• smad
• transcatheter arterial chemoembolization (TACE)
• tumor growth rate (TGR)

• clinical trial
• hepatocellular carcinoma
• immunotherapy

• combined therapy
• hepatocellular carcinoma (HCC)
• portal vein invasion
• sorafenib
• transcatheter arterial chemoembolization (TACE)

• Anti-CTLA-4
• Anti-PD1
• Hepatocellular carcinoma
• Immune checkpoint inhibitors
• Immunotherapy

Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide with limited therapeutic options. Here we report the development of a therapeutic vaccination regimen (shortened as ‘TheraVac’) consisting of intratumoral delivery of high-mobility group nucleosome-binding protein 1 (HMGN1), R848/resiquimod, and one of the checkpoint inhibitors (e.g. anti-CTLA4, anti-PD-L1, or low dose of Cytoxan). C57BL/6 mice harboring large (approximately 1 cm in diameter) established subcutaneous Hepa1-6 hepatomas were cured by intratumoral injections of TheraVac and became tumor-free long-term survivors. Importantly, the resultant tumor-free mice were resistant to re-challenge with Hepa1-6 hepatoma, not B16 melanoma, demonstrating the acquisition of hepatoma-specific immunity in the absence of any administered tumor antigen. Mechanistic studies showed that upon treatment with TheraVac, Hepa1-6-bearing mice generated increased Hepa1-6-specific CTLs in the draining lymph nodes and showed greatly upregulated expression of CXCL9, CXCL10, and IFN-γ and elevated infiltration of T lymphocytes in tumor tissues. Treatment of large Hepa1-6 hepatomas on one mouse flank also eliminated smaller (approximately 0.5 cm in diameter) hepatomas implanted on the other flank. Thus, TheraVac has potential as a curative immunotherapeutic regimen for the treatment of human HCC.

• HMGN1
• R848
• anti-CTLA4
• anti-PD-L1
• cytoxan

• 5-FU
• HUMSC
• anti-CD3scfv
• hepatocellular carcinoma
• immunotherapy

• Aged
• Antibodies, Monoclonal/administration & dosage
• Antibodies, Monoclonal/adverse effects
• Antineoplastic Agents/administration & dosage
• Antineoplastic Agents/adverse effects
• B7-H1 Antigen/metabolism
• Biomarkers, Tumor/metabolism
• Carcinoma, Hepatocellular/drug therapy
• Carcinoma, Hepatocellular/pathology
• Dose-Response Relationship, Drug
• Drug Administration Schedule
• Female
• Humans
• Liver Neoplasms/drug therapy
• Liver Neoplasms/pathology
• Male
• Nivolumab
• Response Evaluation Criteria in Solid Tumors
• Time Factors
• Treatment Outcome
• Tumor Burden