• advanced lung adenocarcinoma
• bevacizumab
• chemotherapy
• driver gene-negative
• programmed cell death protein 1/programmed death-ligand 1 inhibitor

Hepatitis B virus (HBV) infection plays an important role in the occurrence and development of hepatocellular carcinoma (HCC), and the rate of HBV infection in liver cancer patients in China is as high as 92.05%. Due to long-term exposure to chronic antigens from the gut, the liver needs to maintain a certain level of immune tolerance, both to avoid severe inflammation caused by non-pathogenic antigens and to maintain the possibility of rapid and violent responses to infection and tumors. Therefore, HBV infection interacts with the tumor microenvironment (TME) through a highly complex and intertwined signaling pathway, which results in a special TME in HCC. Due to changes in the TME, tumor cells can evade immune surveillance by inhibiting tumor-specific T cell function through cytotoxic T-lymphocy-associated protein-4 (CTLA-4) and programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1). Interferons, as a class of immune factors with strong biological activity, can improve the TME of HBV-HCC through various pathways. In recent years, the systematic treatment of HCC has gradually come out of the dilemma. In addition to the continuous emergence of new multi-target anti-vascular tyrosine kinase inhibitor drugs, immune checkpoint inhibitors have opened up a new avenue for the systematic treatment of HCC. At present, immunotherapy based on PD-1/L1 inhibitors has gradually become a new direction of systematic treatment for HCC, and the disease characteristics of patients included in global clinical studies are different from those of Chinese patients. Therefore, whether a group of HCC patients with HBV background and poor prognosis in China can also benefit from immunotherapy is an issue of wide concern. This review aims to elucidate the advances of immunotherapy for HBV related HCC patients with regard to: (1) Immunotherapy based on interferons; (2) Immunotherapy based on PD-1/L1 inhibitors; (3) Immunotherapy based on CTLA4 inhibitors; (4) Adoptive cell transfer; (5) Combination immunotherapy strategy; and (6) Shortcomings of immunotherapy.

• Hepatitis B virus
• Hepatocellular carcinoma
• Immune checkpoint inhibitors
• Peginterferon alpha
• Systematic treatment

Hepatitis B virus (HBV) infection plays an important role in the occurrence and development of hepatocellular carcinoma (HCC), and the rate of HBV infection in liver cancer patients in China is as high as 92.05%. Due to long-term exposure to chronic antigens from the gut, the liver needs to maintain a certain level of immune tolerance, both to avoid severe inflammation caused by non-pathogenic antigens and to maintain the possibility of rapid and violent responses to infection and tumors. Therefore, HBV infection interacts with the tumor microenvironment (TME) through a highly complex and intertwined signaling pathway, which results in a special TME in HCC. Due to changes in the TME, tumor cells can evade immune surveillance by inhibiting tumor-specific T cell function through cytotoxic T-lymphocy-associated protein-4 (CTLA-4) and programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1). Interferons, as a class of immune factors with strong biological activity, can improve the TME of HBV-HCC through various pathways. In recent years, the systematic treatment of HCC has gradually come out of the dilemma. In addition to the continuous emergence of new multi-target anti-vascular tyrosine kinase inhibitor drugs, immune checkpoint inhibitors have opened up a new avenue for the systematic treatment of HCC. At present, immunotherapy based on PD-1/L1 inhibitors has gradually become a new direction of systematic treatment for HCC, and the disease characteristics of patients included in global clinical studies are different from those of Chinese patients. Therefore, whether a group of HCC patients with HBV background and poor prognosis in China can also benefit from immunotherapy is an issue of wide concern. This review aims to elucidate the advances of immunotherapy for HBV related HCC patients with regard to: (1) Immunotherapy based on interferons; (2) Immunotherapy based on PD-1/L1 inhibitors; (3) Immunotherapy based on CTLA4 inhibitors; (4) Adoptive cell transfer; (5) Combination immunotherapy strategy; and (6) Shortcomings of immunotherapy.

• Hepatitis B virus
• Hepatocellular carcinoma
• Immune checkpoint inhibitors
• Peginterferon alpha
• Systematic treatment

• HBV-specific T-cell response
• hepatitis B virus
• hepatocellular carcinoma
• immune response

• Carcinoma, Hepatocellular/immunology
• Carcinoma, Hepatocellular/virology
• Humans
• Liver Neoplasms/immunology
• Liver Neoplasms/virology
• Hepatitis B virus/immunology
• Adaptive Immunity
• T-Lymphocytes, Regulatory/immunology
• Programmed Cell Death 1 Receptor/immunology
• Immune Checkpoint Inhibitors/therapeutic use
• Immune Checkpoint Inhibitors/pharmacology
• Hepatitis B/immunology
• Hepatitis B/virology
• Hepatitis B/complications
• Hepatitis B, Chronic/immunology
• Hepatitis B, Chronic/virology
• Hepatitis B, Chronic/complications
• CD4-Positive T-Lymphocytes/immunology
• T-Lymphocytes/immunology
• Immunotherapy

• Anti-IL-17A
• Anti-PD-L1
• Combination therapy
• Immunotherapy Checkpoint blockade
• Liver cancer

• Humans
• Carcinoma, Hepatocellular/drug therapy
• Carcinoma, Hepatocellular/metabolism
• Liver Neoplasms/drug therapy
• Liver Neoplasms/metabolism
• CD8-Positive T-Lymphocytes
• B7-H1 Antigen/metabolism
• Th17 Cells/metabolism
• Immunotherapy/methods
• Antibodies, Monoclonal/metabolism
• Tumor Microenvironment

• Humans
• Carcinoma, Hepatocellular
• Hepatitis B virus
• Immunophenotyping
• Liver Neoplasms
• Tumor Microenvironment

• HCC
• IL-36
• IL-37
• TAM
• pathogenesis

• Animals
• Humans
• Carcinoma, Hepatocellular/pathology
• Liver Neoplasms/pathology
• Cytokines/therapeutic use
• Liver Cirrhosis/drug therapy
• Anti-Inflammatory Agents/therapeutic use

• CD4+ T cells
• CD8+ T cells
• Hepatocellular carcinoma
• Programmed cell death protein 1
• T cell immunoglobulin and mucin domain-containing protein 3

• biomarker
• clinical response
• hepatocellular carcinoma
• immune checkpoint inhibition
• immune monitoring
• liver transplantation
• rejection risk

• PD-1 inhibitor
• PD-L1 inhibitor
• PET/CT
• metabolic tumor volume
• prognostic model
• unresectable hepatocellular carcinoma

• National Key Research and Development Program of China
• National Natural Science Foundation of China
• Chinese Academy of Medical Sciences (CAMS) Innovation Fund for Medical Sciences

• PD-1 inhibitor
• PD-L1 inhibitor
• hepatocellular carcinoma
• immune checkpoint
• immunotherapy
• tumor immune escape

• Humans
• Carcinoma, Hepatocellular/drug therapy
• Carcinoma, Hepatocellular/metabolism
• Liver Neoplasms/drug therapy
• Immune Checkpoint Inhibitors/therapeutic use
• Immune Checkpoint Inhibitors/pharmacology
• B7-H1 Antigen/metabolism
• Immunotherapy/methods
• Tumor Microenvironment

Phosphogluconate dehydrogenase (PGD) is involved in the regulation of various tumors. However, its role in hepatocellular carcinoma (HCC) is poorly understood. This study tried to determine the prognostic efficacy of PGD and its value for immunotherapy in HCC.

The data from the TCGA database was used to explore the predictive power of PGD expression and methylation on the overall survival (OS) of HCC through Cox regression and the Kaplan-Meier analysis. Then, we used the GEO and ICGC database to further verify the predictive power. Finally, the relationship between PGD and immune cells and the relationship between PGD and the efficacy of immunotherapy were explored through bioinformatics analysis in HCC.

PGD is highly expressed in HCC tissues, which is negatively regulated by PGD methylation. Low PGD expression and PGD hypermethylation predict better OS in HCC patients. Besides, a meta-analysis based on the TCGA, GSE14520, and ICGC databases further confirms that low PGD expression is closely related to favorable OS. Then, we find significant differences of immune cell infiltrations between high and low PGD expression groups. Expressions of immune checkpoints, most HLA members and tumor mutation burden (TMB) are higher in the high PGD expression group, which indicates beneficial efficacy of immunotherapy in this group. And the potential mechanisms of PGD are exhibited.

PGD is an independent prognostic factor of HCC patients and plays an important role in immune cell infiltration and immunotherapy, which indicates that PGD can be used as a predictive biomarker for HCC immunotherapy.

• National Natural Science Foundation of China

• Amino acids
• Hepatocellular carcinoma
• Metabolism
• T cell function
• Tumor microenvironment

• National Natural Science Foundation of China

We aimed to characterize serine protease inhibitor Kazal type 1 (SPINK1) as a gene signature for the early diagnosis, molecular targeting, and prediction of immune checkpoint blockade (ICB) treatment response of hepatocellular carcinoma (HCC).

The transcriptomics, proteomics, and phenotypic analyses were performed separately or in combination.

We obtained the following findings on SPINK1. Firstly, in the transcriptomic training dataset, which included 279 stage I and II tumor samples (out of 1,884 stage I–IV HCC specimens) and 259 normal samples, significantly higher area under curve (AUC) values and increased integrated discrimination improvement (IDI) and net reclassification improvement (NRI) were demonstrated for HCC discrimination in SPINK1-associated models compared with those of alpha-fetoprotein (AFP). The calibration of both SPINK1-related curves fitted significantly better than that of AFP. In the two independent transcriptomic validation datasets, which included 201, 103 stage I-II tumor and 192, 169 paired non-tumor specimens, respectively, the obtained results were consistent with the above-described findings. In the proteomic training dataset, which included 98 stage I and II tumor and 165 normal tissue samples, the analyses also revealed better AUCs and increased IDI and NRI in the aforementioned SPINK1-associated settings. A moderate calibration was shown for both SPINK1-associated models relative to the poor results of AFP. Secondly, in the in vitro and/or in vivo murine models, the wet-lab experiments demonstrated that SPINK1 promoted the proliferation, clonal formation, migration, chemoresistance, anti-apoptosis, tumorigenesis, and metastasis of HCC cells, while the anti-SPINK1 antibody inhibited the growth of the cells, suggesting that SPINK1 has “tumor marker” and “targetable” characteristics in the management of HCC. The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses revealed that SPINK1 was engaged in immunity-related pathways, including T-cell activation. Thirdly, in the transcriptomic analyses of the 368 HCC specimens from The Cancer Genome Atlas (TCGA) cohort, the high abundance of SPINK1 was positively correlated with the high levels of activated tumor-infiltrating CD4⁺ and CD8⁺ T lymphocytes and dendritic and natural killer cells, while there were also positive correlations between SPINK1 and immune checkpoints, including PD-1, LAG-3, TIM-3, TIGIT, HAVCR2, and CTLA-4. The ESTIMATE algorithm calculated positive correlations between SPINK1 and the immune and ESTIMATE scores, suggesting a close correlation between SPINK1 and the immunogenic microenvironment within HCC tissues, which may possibly help in predicting the response of patients to ICB therapy.

SPINK1 could be a potential biomarker for the early detection, targeted therapy, and prediction of ICB treatment response in the management of HCC.

• Animals
• Carcinoma, Hepatocellular/diagnosis
• Carcinoma, Hepatocellular/drug therapy
• Carcinoma, Hepatocellular/genetics
• Early Detection of Cancer
• Humans
• Immune Checkpoint Inhibitors/pharmacology
• Immune Checkpoint Inhibitors/therapeutic use
• Liver Neoplasms/diagnosis
• Liver Neoplasms/drug therapy
• Liver Neoplasms/genetics
• Mice
• Proteomics
• Trypsin Inhibitor, Kazal Pancreatic/genetics
• Trypsin Inhibitor, Kazal Pancreatic/metabolism
• Tumor Microenvironment
• alpha-Fetoproteins

• Antibodies, Monoclonal, Humanized
• Carcinoma, Hepatocellular/drug therapy
• Chemoembolization, Therapeutic
• Humans
• Liver Neoplasms/drug therapy
• Neoplasm Staging
• Phenylurea Compounds
• Prospective Studies
• Quinolines
• Retrospective Studies
• Treatment Outcome

• NAFLD
• NASH
• PD-1
• immune therapy
• liver immune microenvironment

• B7-H1 Antigen/metabolism
• Carcinoma, Hepatocellular/drug therapy
• Humans
• Liver Neoplasms/pathology
• Non-alcoholic Fatty Liver Disease/drug therapy
• Programmed Cell Death 1 Receptor/metabolism

Doxorubicin (DOX) is a potent chemotherapeutic agent; however, it causes severe heart injury via apoptosis induction in many patients. DOX-induced cardiotoxicity is attenuated by activated autophagy in the heart. We previously found that programmed cell death 1 (Pdcd1), an immune checkpoint receptor, inhibits DOX-induced cardiomyocyte apoptosis. In this study, we investigated whether autophagy contributes to the protective role of Pdcd1 against DOX-induced cardiomyocyte apoptosis. We also examined the role of Pdcd1 in DOX-induced apoptosis in cancer cells. Rat cardiomyocyte cell line H9c2 and human cancer cell lines K562 and MCF-7 were transfected with Pdcd1-encoding plasmid DNA to establish Pdcd1-overexpressing cells. Apoptosis and autophagy were determined using a luciferase assay. In H9c2 cells, DOX-induced apoptosis and viability reduction occurred through caspase activation. In particular, Pdcd1 overexpression activated the autophagy pathway through the inhibition of the mammalian target of rapamycin, a major negative regulator of autophagy. Moreover, it prevented DOX-induced cardiomyocyte apoptosis; a similar cardioprotection was observed when normal H9c2 cells (without Pdcd1 overexpression) were treated with rapamycin, an autophagy inducer, before the DOX treatment. Conversely, in cancer cells, Pdcd1 overexpression increased both basal and DOX-induced apoptosis. The role of Pdcd1 in DOX-induced apoptosis in cardiomyocytes and cancer cells was opposing. Pdcd1 signaling prevented DOX-induced apoptosis in cardiomyocytes, through autophagy induction; it enhanced DOX-induced apoptosis in cancer cells. Therefore, Pdcd1 could be a critical molecule for more effective and safer DOX chemotherapy.

• Apoptosis
• Autophagy
• Cardiomyocyte
• Cardiotoxicity
• Doxorubicin
• Programed cell death 1

Hepatocellular carcinoma (HCC) is a notoriously difficult cancer to treat. The recent development of immune checkpoint inhibitors has revolutionised HCC therapy; however, successful response is only observed in a small percentage of patients. Biomarkers typically used to predict treatment response in other tumour types are ineffective in HCC, which arises in an immune-suppressive environment. However, imaging markers that measure changes in tumour infiltrating immune cells may supply information that can be used to determine which patients are responding to therapy posttreatment. We have evaluated [¹⁸F]AlF-mNOTA-GZP, a radiolabeled peptide targeting granzyme B, to stratify response to ICIs in a HEPA 1-tumours, a syngeneic model of HCC. Posttherapy, in vivo tumour retention of [¹⁸F]AlF-mNOTA-GZP was correlated to changes in tumour volume and tumour-infiltrating immune cells. [¹⁸F]AlF-mNOTA-GZP successfully stratified response to immune checkpoint inhibition in the syngeneic HEPA 1-6 model. FACS indicated significant changes in the immune environment including a decrease in immune suppressive CD4+ T regulatory cells and increases in tumour-associated GZB+ NK+ cells, which correlated well with tumour radiopharmaceutical uptake. While the immune response to ICI therapies differs in HCC compared to many other cancers, [¹⁸F]AlF-mNOTA-GZP retention is able to stratify response to ICI therapy associated with tumour infiltrating GZB+ NK+ cells in this complex tumour microenvironment.