• CD4 T lymphocytes
• T CD4 tumor response
• cancer
• tissue-specific immune response
• tumor immunology

• Animals
• Humans
• Adaptation, Physiological/immunology
• CD4-Positive T-Lymphocytes/immunology
• Cytokines/metabolism
• Cytokines/immunology
• Homeostasis/immunology
• Neoplasms/immunology
• Neoplasms/pathology
• Tumor Microenvironment/immunology

• drug-eluting beads transarterial chemoembolization
• hepatocellular carcinoma
• immunotherapy
• soluble programmed cell death protein 1

• Interventional oncology research fund

• Adoptive cell therapies
• CIK cell therapy
• Cancer treatment
• Colorectal cancer
• Cytokine induced killer cells
• Immunotherapy
• NK T cells

• Humans
• Immunotherapy, Adoptive/methods
• Combined Modality Therapy
• Colorectal Neoplasms/therapy
• Cytokines
• Cell- and Tissue-Based Therapy

• Adaptive immune cell
• Hepatocellular carcinoma
• Immunotherapy
• Innate immune cell
• Tumor immune microenvironment

• Humans
• Carcinoma, Hepatocellular/therapy
• Liver Neoplasms/therapy
• Immunotherapy
• CD8-Positive T-Lymphocytes
• Bevacizumab
• Tumor Microenvironment

• 82260535 National Natural Science Foundation of China
• gyfynsfc-2022-07 National Natural Science Foundation (Cultivation Project of General Program) of Guizhou Medical University
• gyfynsfc-2021-34 National Natural Science Foundation of China (NSFC) Cultivation Program of Affiliated Hospital of Guizhou Medical University

• Humans
• B7-H1 Antigen/metabolism
• Biomarkers, Tumor/metabolism
• Carcinoma, Hepatocellular/pathology
• Immunotherapy/methods
• Ligands
• Liver Neoplasms/pathology
• Tumor Microenvironment
• Programmed Cell Death 1 Receptor/metabolism

• Cytokine-induced killer cells
• Hepatocellular carcinoma
• Meta-analysis

• Combination therapy
• Hepatocellular carcinoma
• Immune checkpoint inhibitors

• PD-1/PD-L1
• combined therapy
• hepatocellular carcinoma
• immune checkpoint inhibition
• immunotherapy
• liver cancer
• vaccine

Hepatocellular carcinoma (HCC), one of the most common and lethal tumors worldwide, is usually not diagnosed until the disease is advanced, which results in ineffective intervention and unfavorable prognosis. Small molecule targeted drugs of HCC, such as sorafenib, provided only about 2.8 months of survival benefit, partially due to cancer stem cell resistance. There is an urgent need for the development of new treatment strategies for HCC. Tumor immunotherapies, including immune check point inhibitors, chimeric antigen receptor T cells (CAR-T) and bispecific antibodies (BsAb), have shown significant potential. It is known that the expression level of glypican-3 (GPC3) was significantly increased in HCC compared with normal liver tissues. A bispecific antibody (GPC3-S-Fabs) was reported to recruit NK cells to target GPC3 positive cancer cells. Besides, bispecific T-cell Engagers (BiTE), including GPC3/CD3, an aptamer TLS11a/CD3 and EpCAM/CD3, were recently reported to efficiently eliminate HCC cells. It is known that immune checkpoint proteins programmed death-1 (PD-1) binding by programmed cell death-ligand 1 (PD-L1) activates immune checkpoints of T cells. Anti-PD-1 antibody was reported to suppress HCC progression. Furthermore, GPC3-based HCC immunotherapy has been shown to be a curative approach to prolong the survival time of patients with HCC in clinically trials. Besides, the vascular endothelial growth factor (VEGF) inhibitor may inhibit the migration, invasion and angiogenesis of HCC. Here we review the cutting-edge progresses on mechanisms and clinical trials of HCC immunotherapy, which may have significant implication in our understanding of HCC and its immunotherapy.

• aptamer
• bispecific T-cell Engagers
• bispecific antibody
• hepatocellular carcinoma
• immunotherapy
• vascular endothelial growth factor (VEGF)

• adaptive cell transfer-based therapy
• chimeric antigen receptor
• chronic hepatitis
• cytokine-induced killer
• fibrosis
• hepatocellular carcinoma
• immune checkpoint inhibitor
• immunotherapy
• molecular target agent
• tumor microenvironment

• RECK
• angiogenesis
• hepatocellular carcinoma
• immune checkpoint inhibitors
• immunotherapy

• hepatocellular carcinoma
• immune checkpoint
• prognosis
• recurrence
• tumor biology

• Adult
• Carcinoma, Hepatocellular/blood
• Carcinoma, Hepatocellular/mortality
• Carcinoma, Hepatocellular/surgery
• Disease-Free Survival
• Female
• Humans
• Liver Neoplasms/blood
• Liver Neoplasms/mortality
• Liver Neoplasms/surgery
• Liver Transplantation/methods
• Liver Transplantation/mortality
• Living Donors
• Male
• Middle Aged
• Multivariate Analysis
• Predictive Value of Tests
• Preoperative Period
• Prognosis
• Programmed Cell Death 1 Receptor/blood
• Reference Values
• Retrospective Studies
• Treatment Outcome

• 2019-01 Korean Society of Hepato-Biliary Pancreatic Surgery

The cytotoxic T cell response against hepatocellular carcinoma antigens is exhausted and fails in its task of deleting tumoral cells. These cells are featured by the expression of negative immune checkpoints that can be modulated to restore T cell function. The blockade of the PD-1/PD-L1 pathway has shown promising results in rescuing hepatocellular carcinoma-specific CD8 T cells but only a reduced group of cases is sensitive to this treatment and the effect is usually temporary. Therefore, new anti-PD-1 based combinatory strategies are underway to increase the response by adding the effect of blocking neo-angiogenesis and other negative immune checkpoints, boosting positive immune checkpoints, blocking suppressive cytokines, or inducing the expression of tumoral neoantigens. The restoration of T cell responses with these anti-PD-1 based combinatory therapies will change the outcome of advanced hepatocellular carcinoma.

Thirty to fifty percent of hepatocellular carcinomas (HCC) display an immune class genetic signature. In this type of tumor, HCC-specific CD8 T cells carry out a key role in HCC control. Those potential reactive HCC-specific CD8 T cells recognize either HCC immunogenic neoantigens or aberrantly expressed host’s antigens, but they become progressively exhausted or deleted. These cells express the negative immunoregulatory checkpoint programmed cell death protein 1 (PD-1) which impairs T cell receptor signaling by blocking the CD28 positive co-stimulatory signal. The pool of CD8 cells sensitive to anti-PD-1/PD-L1 treatment is the PD-1dim memory-like precursor pool that gives rise to the effector subset involved in HCC control. Due to the epigenetic imprints that are transmitted to the next generation, the effect of PD-1 blockade is transient, and repeated treatments lead to tumor resistance. During long-lasting disease, besides the TCR signaling impairment, T cells develop other failures that should be also set-up to increase T cell reactivity. Therefore, several PD-1 blockade-based combinatory therapies are currently under investigation such as adding antiangiogenics, anti-TGFβ1, blockade of other negative immune checkpoints, or increasing HCC antigen presentation. The effect of these combinations on CD8⁺ T cells is discussed in this review.

• CD8 T cell response
• PD-1
• PD-L1
• combination therapy
• hepatocellular carcinoma
• immune check-point inhibitor
• immunotherapy

There is no study accessible now assessing the prognostic aspect of radiomics for anti-PD-1 therapy for patients with HCC.

The aim of this study was to develop and validate a radiomics nomogram by incorporating the pretreatment contrast-enhanced Computed tomography (CT) images and clinical risk factors to estimate the anti-PD-1 treatment efficacy in Hepatocellular Carcinoma (HCC) patients.

A total of 58 patients with advanced HCC who were refractory to the standard first-line of therapy, and received PD-1 inhibitor treatment with Toripalimab, Camrelizumab, or Sintilimab from 1st January 2019 to 31 July 2020 were enrolled and divided into two sets randomly: training set (n = 40) and validation set (n = 18). Radiomics features were extracted from non-enhanced and contrast-enhanced CT scans and selected by using the least absolute shrinkage and selection operator (LASSO) method. Finally, a radiomics nomogram was developed based on by univariate and multivariate logistic regression analysis. The performance of the nomogram was evaluated by discrimination, calibration, and clinical utility.

Eight radiomics features from the whole tumor and peritumoral regions were selected and comprised of the Fusion Radiomics score. Together with two clinical factors (tumor embolus and ALBI grade), a radiomics nomogram was developed with an area under the curve (AUC) of 0.894 (95% CI, 0.797–0.991) and 0.883 (95% CI, 0.716–0.998) in the training and validation cohort, respectively. The calibration curve and decision curve analysis (DCA) confirmed that nomogram had good consistency and clinical usefulness.

This study has developed and validated a radiomics nomogram by incorporating the pretreatment CECT images and clinical factors to predict the anti-PD-1 treatment efficacy in patients with advanced HCC.

• computed tomography
• hepatocellular carcinoma
• nomogram
• programmed death receptor-1
• radiomics

• Programmed cell death-1
• alpha-fetoprotein
• disease-free survival
• hepatocellular carcinoma
• meta-analysis
• prognosis

• Carcinoma, Hepatocellular/genetics
• Disease-Free Survival
• Humans
• Liver Neoplasms/genetics
• Prognosis
• Proportional Hazards Models

• clinicopathological features
• hepatocellular carcinoma
• prognosis
• programmed cell death-1

• genetic alteration
• hepatocellular carcinoma
• immune checkpoint inhibitor
• immune phenotype
• molecular classification
• oncogenic signal
• stem cell marker
• β-catenin

• 18K07922 a Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science
• 18 Smoking Research Foundation

• HCC
• PD-L1
• clinicopathology
• meta-analysis
• prognosis
• survival

• B7-H1 Antigen/analysis
• B7-H1 Antigen/immunology
• B7-H1 Antigen/metabolism
• Biomarkers, Tumor/analysis
• Biomarkers, Tumor/metabolism
• Carcinoma, Hepatocellular/immunology
• Carcinoma, Hepatocellular/mortality
• Carcinoma, Hepatocellular/pathology
• Carcinoma, Hepatocellular/therapy
• Cell Membrane/metabolism
• Disease-Free Survival
• Hepatectomy
• Humans
• Immunotherapy
• Liver/cytology
• Liver/immunology
• Liver/pathology
• Liver/surgery
• Liver Neoplasms/immunology
• Liver Neoplasms/mortality
• Liver Neoplasms/pathology
• Liver Neoplasms/therapy
• Neoplasm Recurrence, Local/epidemiology
• Neoplasm Recurrence, Local/immunology
• Neoplasm Recurrence, Local/pathology
• Prognosis

• CAR-T therapy
• Cancer vaccine
• Immune checkpoint inhibitor
• PD-1
• Targeting drug

Immunotherapies targeting immune checkpoints are fast-developing therapeutic approaches adopted for several tumor types that trigger unprecedented rates of durable clinical responses. Immune checkpoint programmed cell death protein 1 (PD-1), expressed primarily by T cells, and programmed cell death ligand 1 (PD-L1), expressed mainly by tumor cells, macrophages, and dendritic cells, are molecules that impede immune function, thereby allowing tumor cells to proliferate, grow and spread. PD-1/PD-L1 checkpoint inhibitors have emerged as a promising treatment strategy of hepatocellular carcinoma (HCC). However, only a minority of HCC patients benefit from this therapy. To find a niche for immune checkpoint inhibition in HCC patients, future strategies might require predictive factor-based patient selection, to identify patients who are likely to respond to the said therapy and combination strategies in order to enhance anti-tumor efficacy and clinical success. This review provides an overview of the most recent data pertaining to predictive factors for response to PD-1/PD-L1 checkpoint inhibition in the field of HCC.

• PD-1
• PD-L1
• hepatocellular carcinoma
• immune checkpoint inhibition
• immunotherapy
• predictive factors

Hepatitis B virus (HBV) has been recognized as a leading cause of hepatocellular carcinoma (HCC). Numerous reports suggest that immune infiltration can predict the prognosis of HCC. Nonetheless, no creditable markers for prognosis of HBV-related HCC have been established by systematically assessing the immune-related markers based on tumor transcriptomes.

To establish an immune-related marker based on the cell compositions of immune infiltrate obtained based on tumor transcriptomes, so as to enhance the prediction accuracy of HBV-related HCC prognosis.

RNA expression patterns as well as the relevant clinical data of HCC patients were obtained from The Cancer Genome Atlas. Twenty-two immunocyte fraction types were estimated by cell type identification by estimating relative subsets of RNA transcripts. Subsequently, the least absolute shrinkage and selection operator (LASSO) Cox regression model was employed to construct an immunoscore based on the immunocyte fraction types. Afterwards, the receiver operating characteristic (ROC) curve, Kaplan-Meier, and multivariate Cox analyses were performed. Additionally, a nomogram for prognosis that integrated the immunoscore as well as the clinical features was established. Meanwhile, the correlation of immunoscore with immune genes was also detected, and gene set enrichment analysis (GSEA) of the immunoscore was conducted.

A total of 22 immunocyte fraction types were predicted and compared among the tumor as well as non-tumor samples. An immunoscore was constructed through adopting the LASSO model, which contained eight immunocyte fraction types. Meanwhile, the areas under the ROC curves for the immunoscore biomarker prognostic model were 0.971, 0.912, and 0.975 for 1-, 3-, and 5-year overall survival (OS), respectively. Difference in OS between the high-immunoscore group and the low-immunoscore group was statistically significant [hazard ratio (HR) = 66.007, 95% confidence interval (CI): 8.361-521.105; P < 0.0001]. Moreover, multivariable analysis showed that the immunoscore was an independent factor for predicting the prognosis (HR = 2.997, 95%CI: 1.737-5.170). A nomogram was established, and the C-index was 0.757 (95%CI: 0.648-0.866). The immunoscore showed a significant negative correlation with the expression of PD-1 (P = 0.024), PD-L1 (P = 0.026), PD-L2 (P = 0.029), and CD27 (P = 0.033). Eight pathways were confirmed by GSEA.

The established immunoscore can potentially serve as a candidate marker to estimate the OS for HBV-related HCC cases.

• Immune risk score
• Hepatitis B virus
• Hepatocellular carcinoma
• Prognostic signature
• Cell type identification by estimating relative subsets of RNA transcripts

• Adult
• Aged
• Carcinoma, Hepatocellular/immunology
• Carcinoma, Hepatocellular/mortality
• Carcinoma, Hepatocellular/virology
• Datasets as Topic
• Female
• Gene Expression Profiling
• Hepatitis B virus/immunology
• Humans
• Kaplan-Meier Estimate
• Liver/cytology
• Liver/immunology
• Liver/pathology
• Liver Neoplasms/immunology
• Liver Neoplasms/mortality
• Liver Neoplasms/virology
• Lymphocytes, Tumor-Infiltrating/immunology
• Lymphocytes, Tumor-Infiltrating/metabolism
• Male
• Middle Aged
• Nomograms
• Prognosis
• ROC Curve
• Transcriptome/immunology

• Adoptive cell transfer
• Hepatocellular carcinoma (HCC)
• Immune checkpoint blockade (ICB)
• Immunotherapy
• Oncolytic virus

• Cytokine-induced killer cells
• Dendritic cells
• Hepatocellular carcinoma
• Immunotherapy

• Carcinoma, Hepatocellular/immunology
• Carcinoma, Hepatocellular/mortality
• Carcinoma, Hepatocellular/therapy
• Clinical Trials as Topic
• Combined Modality Therapy/adverse effects
• Combined Modality Therapy/methods
• Cytokine-Induced Killer Cells/immunology
• Cytokine-Induced Killer Cells/transplantation
• Dendritic Cells/immunology
• Dendritic Cells/transplantation
• Feasibility Studies
• Humans
• Immunotherapy, Adoptive/adverse effects
• Immunotherapy, Adoptive/methods
• Liver Neoplasms/immunology
• Liver Neoplasms/mortality
• Liver Neoplasms/therapy
• Neoplasm Recurrence, Local/epidemiology
• Neoplasm Recurrence, Local/immunology
• Neoplasm Recurrence, Local/prevention & control
• Prognosis
• Survival Analysis
• Treatment Outcome

A series of studies has investigated the prognostic role and clinical significance of programmed death ligand 1 (PD-L1) in hepatocellular carcinoma (HCC). However, the results were inconsistent. We aimed to clarify the prognostic role of PD-L1 and relationship between PD-L1 expression and several important clinicopathological features.

PubMed, EMBASE and the Science Citation Index Expanded were systematically searched. All cohort or case–control studies comparing the prognosis and clinical features between the high PD-L1 and low PD-L1 groups were included. Publication bias was evaluated using funnel plots and Begg’s test. Subgroup analysis, sensitivity analysis and meta-regression analysis were performed.

Seventeen studies including 2979 patients were eligible. The overall survival (OS) was not significantly different between the high and low PD-L1 groups (hazard ratio [HR]: 1.27; 95% confidence interval [CI] 0.98–1.65: P = 0.07) with significant heterogeneity (P < 0.001; I² = 81%). The recurrence-free survival (RFS) was not significantly different between the high and low PD-L1 groups (HR: 1.22; 95% CI 0.97–1.53; P = 0.09) with significant heterogeneity (P < 0.001; I² = 78%). The expression of PD-L1 was found to be significantly correlated with alpha-fetoprotein, hepatitis history, and tumour-infiltrating lymphocytes. Begg’s test found no significant publication bias for OS and RFS. Sensitivity analysis established the robustness of our results. Subgroup analysis and meta-regression analysis found the region of research as a significant contributor to inter-study heterogeneity in RFS, indicating some racial differences in the prognostic role of PD-L1.

Our study found no significant prognostic role of PD-L1 in HCC patients after potential curative hepatectomy based on our included studies. The expression of PD-L1 was significantly correlated with AFP, hepatitis history, and TILs. The prognostic role of PD-L1 in HCC warrants further investigation.

The online version of this article (10.1186/s12935-019-0738-9) contains supplementary material, which is available to authorized users.

• Clinicopathological features
• HCC
• PD-L1
• Prognosis

• cd8
• clinicopathologic
• hepatocellular carcinoma
• prognosis

• CD8-Positive T-Lymphocytes/pathology
• Carcinoma, Hepatocellular/diagnosis
• Carcinoma, Hepatocellular/mortality
• Carcinoma, Hepatocellular/pathology
• Humans
• Liver Neoplasms/diagnosis
• Liver Neoplasms/mortality
• Liver Neoplasms/pathology
• Lymphocytes, Tumor-Infiltrating/pathology
• Prognosis

Blocking the programmed death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) pathway in hepatocellular carcinoma (HCC) is a very promising approach in immunotherapy. However, the correlation and prognostic values of serum soluble PD-1 and PD-L1 (sPD-1/sPD-L1) have not been explored conjointly in HCC patients.

This study retrospectively included 120 HCC patients receiving radical resection. The serum levels of sPD-1/sPD-L1 and inflammatory cytokines were measured by antibody array assay. Immunohistochemistry was applied to assess both the expression of membrane-bound PD-L1, and the number of CD4⁺ tumor-infiltrating lymphocytes (TILs) and CD8⁺ TILs.

The best cut-off values of sPD-1 and sPD-L1 for predicting disease-free survival (DFS) were 33.0 µg/ml and 11.2 µg/ml, respectively. Multivariable analysis showed that sPD-L1 was a negative independent prognostic factor [DFS, Hazard Ratio (HR) 2.58, 95% CI 1.14–5.84, P = 0.023; overall survival (OS), HR 1.77, 95% CI 1.01–3.12, P = 0.048], while sPD-1 was a favorable independent prognostic factor (DFS, HR 0.32, 95% CI 0.14–0.74, P = 0.007; OS, HR 0.54, 95% CI 0.30–0.98, P = 0.044) in HCC patients. We also observed some similar associations between inflammatory cytokines (IL-10, IL-17, TNF-α) and sPD-1 or sPD-L1, as well as a close positive association between sPD-1 and sPD-L1. No significant associations of sPD-1/sPD-L1 with either intra-tumoral PD-L1 expression, or the numbers of CD4⁺ TILs and CD8⁺ TILs were determined.

Our findings indicate that sPD-1 and sPD-L1 are independent prognostic factors with opposite prognostic roles in predicting both DFS and OS in HCC patients.

The online version of this article (10.1007/s00262-018-2271-4) contains supplementary material, which is available to authorized users.

• Immune checkpoint
• Immunohistochemistry
• Inflammatory cytokines
• Tumor-infiltrating lymphocytes

• Checkpoint inhibitors
• Hepatocellular carcinoma
• Immunotherapy
• Ligand programmed death-ligand-1
• Programmed cell death protein-1

• PD-1
• PD-L1
• gastrointestinal tract cancers
• immunotherapies