Immune Checkpoint Inhibitors In Hepatocellular Carcinoma Research Articles

Efficacy of radiotherapy combined with hepatic arterial infusion chemotherapy, TKI and ICI for hepatocellular carcinoma with portal vein tumor thrombus: a retrospective cohort study.

This retrospective study was conducted to evaluate the effectiveness and safety of a new combination therapy of radiotherapy (RT), hepatic arterial infusion chemotherapy (HAIC), tyrosine kinase inhibitors (TKI) and immune checkpoint inhibitors (ICI) for hepatocellular carcinoma (HCC) patients involving portal vein tumor thrombus (PVTT). A total of 71 HCC patients with PVTT were retrospectively analyzed: 45 patients were treated by 'HAIC + TKI + ICI' therapy and 26 patients by the new combination therapy. The primary outcomes were overall survival (OS), progression-free survival (PFS), and cumulative survival rate. The PFS in the 'New combination therapy' group was longer than that in the 'HAIC + TKI + ICI' group (HR 0.459, 95%CI 0.253-0.832; P = 0.008). Meanwhile, the OS in the 'New combination therapy' group was also longer than that in the 'HAIC + TKI + ICI' group (HR 0.420, 95%CI 0.198-0.894; P = 0.024). Compared with 'HAIC + TKI + ICI' group patients, the 'New combination therapy' group patients had higher 1-year PFS rate and 1-year OS rate (P = 0.029; P = 0.015). There was no significant difference in the incidence of adverse events between the two groups. The new combination therapy was an effective and safe non-surgical treatment for HCC patients with PVTT and could be considered a preferred therapy option.

Hepatic arterial infusion chemotherapy combined with lenvatinib and PD-1 inhibitors versus lenvatinib and PD-1 inhibitors for HCC refractory to TACE.

The study aims to investigate the efficacy and safety of hepatic arterial infusion chemotherapy (HAIC) combined with lenvatinib and immune checkpoint inhibitors (ICIs) versus lenvatinib and ICIs for hepatocellular carcinoma (HCC) with transarterial chemoembolization (TACE) refractoriness. Patients with intermediate or advanced TACE-refractory HCC who received lenvatinib and ICIs with or without HAIC between 2020 and 2022 were retrospectively reviewed. The tumor response, overall survival (OS), progression-free survival (PFS), and treatment-related adverse events (TRAEs) were evaluated and compared between the two groups. Factors affecting OS and PFS were identified with univariate and multivariate Cox regression analyses. A total of 121 patients were enrolled, with 58 patients assigned to the HAIC-Len-ICI group and 63 patients assigned to the Len-ICI group. A higher objective response rate and disease control rate were found in the HAIC-Len-ICI group than in the Len-ICI group (48.30% vs 23.80%, P=0.005; 87.90% vs 69.80%, P=0.02, respectively). The median OS was 24.0months in the HAIC-Len-ICI group and 13.0months in the Len-ICI group (P=0.001). The median PFS was 13.0months in the HAIC-Len-ICI group and 7.2months in the Len-ICI group (P<0.001). Multivariable analyses suggested that the presence of cirrhosis, Child-Pugh B stage, and HAIC-Len-ICI therapy option were prognostic factors for OS and PFS. The incidences of any grade and grade 3/4 TRAEs were both comparable between the two groups. HAIC combined with lenvatinib and ICIs yielded better OS, PFS, ORR, and DCR than lenvatinib-ICI therapy in patients with HCC refractory to TACE, with manageable adverse events.

Prognostic biomarkers associated with immune checkpoint inhibitors in hepatocellular carcinoma.

The treatment of hepatocellular carcinoma (HCC), particularly advanced HCC, has been a serious challenge. Immune checkpoint inhibitors (ICIs) are landmark drugs in the field of cancer therapy in recent years, which have changed the landscape of cancer treatment. In the field of HCC treatment, this class of drugs has shown good therapeutic prospects. For example, atezolizumab in combination with bevacizumab has been approved as first-line treatment for advanced HCC due to significant efficacy. However, sensitivity to ICI therapy varies widely among HCC patients. Therefore, there is an urgent need to search for determinants of resistance/sensitivity to ICIs and to screen biomarkers that can predict the efficacy of ICIs. This manuscript reviews the research progress of prognostic biomarkers associated with ICIs in HCC in order to provide a scientific basis for the development of clinically individualised precision medication regimens.

Immune checkpoint inhibitors in hepatocellular carcinoma: Areview of current clinical trials.

Hepatocellular carcinoma (HCC) is the most common primary liver cancer with a poor prognosis due to advanced disease presentation or recurrence despite curative-intent resection. Since the approval of sorafenib in 2007, few systemic therapies offered a significant improvement in treatment outcomes. Over the last 3 years, however, rapid advancements in the field of immunotherapy have led to approval of checkpoint inhibitors in 2020 for use in advanced HCC. Since then, a few other clinical trials have shown promising results in the adjuvant and neoadjuvant setting. The objective of this review is to summarize data from existing clinical trials evaluating the use of systemic immune checkpoint inhibitors in HCC and to follow the natural evolution of this development across the metastatic, adjuvant, and neoadjuvant landscapes.

Characteristics and outcomes of immunotherapy-related liver injury in patients with hepatocellular carcinoma versus other advanced solid tumours

Immune-related liver injury (irLI) is commonly observed in patients with cancer treated with immune checkpoint inhibitors (ICIs). We aimed to compare the incidence, clinical characteristics, and outcomes of irLI between patients receiving ICIs for hepatocellular carcinoma (HCC) vs. other solid tumours. Two separate cohorts were included: 375 patients with advanced/unresectable HCC, Child-Pugh A class treated with first-line atezolizumab+bevacizumab from the AB-real study, and a non-HCC cohort including 459 patients treated with first-line ICI therapy from the INVIDIa-2 multicentre study. IrLI was defined as a treatment-related increase of aminotransferase levels after exclusion of alternative aetiologies of liver injury. The incidence of irLI was adjusted for the duration of treatment exposure. In patients with HCC, the incidence of any grade irLI was 11.4% over a median treatment exposure of 4.4 months (95% CI 3.7-5.2) vs. 2.6% in the INVIDIa-2 cohort over a median treatment exposure of 12.4 months (95% CI 11.1-14.0). Exposure-adjusted-incidence of any grade irLI was 22.1 per 100-patient-years in patients with HCC and 2.1 per 100-patient-years in patients with other solid tumours (p <0.001), with median time-to-irLI of 1.4 and 4.7 months, respectively. Among patients who developed irLI, systemic corticosteroids were administered in 16.3% of patients with HCC and 75.0% of those without HCC (p<0.001), and irLI resolution was observed in 72.1% and 58.3%, respectively (p= 0.362). In patients with HCC, rates of hepatic decompensation and treatment discontinuation due to irLI were 7%. Grade 1-2 irLI was associated with improved overall survival only in patients with HCC (hazard ratio 0.53, 95% CI 0.29-0.96). Despite higher incidence and earlier onset, irLI in patients with HCC is characterised by higher rates of remission and lower requirement for corticosteroid therapy (vs. irLI in other solid tumours), low risk of hepatic decompensation and treatment discontinuation, not negatively affecting oncological outcomes. Immune-related liver injury (irLI) is common in patients with cancer receiving immune checkpoint inhibitors (ICIs), but whether irLI is more frequent or it is associated with a worse clinical course in patients with hepatocellular carcinoma (HCC), compared to other tumours, is not known. Herein, we compared characteristics and outcomes of irLI in two prospective cohorts including patients treated with ICIs for HCC or for other oncological indications. irLI is significantly more common and it occurs earlier in patients with HCC, also after adjustment for duration of treatment exposure. However, outcomes of patients with HCC who developed irLI are not negatively affected in terms of requirement for corticosteroid therapy, hepatic decompensation, treatment discontinuation and overall survival.

The progress of research on immune checkpoint inhibitor resistance and reversal strategies for hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors in humans, which is prone to recurrence and metastasis and has a poor prognosis. The occurrence and progression of HCC are closely related to immune elimination, immune homeostasis, and immune escape of the immune system. In recent years, immunotherapy, represented by immune checkpoint inhibitors (ICIs), has shown powerful anti-tumor capabilities in HCC patients. However, there are still some HCC patients who cannot benefit from ICIs treatment due to their innate or acquired drug resistance. Therefore, it is of great practical significance to explore the possible mechanisms of resistance to ICIs in HCC and to use them as a target to design strategies to reverse resistance, to overcome drug resistance in HCC and to improve the prognosis of patients. This article summarizes the possible primary (tumor microenvironment alteration, and signaling pathways, etc.) and acquired (immune checkpoint upregulation) resistance mechanisms in patients with HCC treated with ICIs, and based on this, discusses the status and effectiveness of combination drug strategy to reverse drug resistance, to provide a reference for subsequent related studies and decisions.

Prognostic value of nutritional and inflammatory markers in patients with hepatocellular carcinoma who receive immune checkpoint inhibitors.

The emergence of immune checkpoint inhibitors (ICIs) has provided a new treatment option for patients with hepatocellular carcinoma (HCC). However, further evaluation is needed for determining biomarkers for the use of ICIs. The present study evaluated the prognostic value of certain nutritional and inflammatory markers in patients with HCC who received ICIs. In the present study, the clinical data of 151 patients with HCC who received ICIs at Harbin Medical University Cancer Hospital from January 2019 to December 2021 were collected. The blood parameters of all patients before treatment were collected to evaluate certain nutritional and inflammatory markers, including the prognostic nutrition index (PNI), nutritional risk index (NRI), geriatric NRI (GNRI), systemic immune-inflammation index (SII), systemic inflammation response index (SIRI) and advanced lung cancer inflammation index (ALI). Patients were grouped using the cut-off value calculated using receiver operating characteristic (ROC) curves, and the relationship between these biomarkers and prognosis was evaluated through survival analysis. Furthermore, the prognostic value of these biomarkers was assessed through multivariate Cox regression analysis and construction of nomograms. Finally, time-ROC curves were plotted to compare the differences in predicting prognosis between the biomarkers. In the preliminary survival analysis, all inflammatory and nutritional markers included in the present study were significantly associated with the prognosis of HCC in patients who received ICIs. Similar results were obtained in a subgroup analysis of patients with different Barcelona Clinic Liver Cancer (BCLC) stages. Multivariate Cox regression analysis demonstrated that GNRI, PNI, BCLC stage and Tumor-Node-Metastasis (TNM) stage were significantly associated with progression-free survival (PFS), whereas GNRI, BCLC stage and TNM stage were also significantly associated with overall survival (OS). Furthermore, the time-ROC curves indicated that nutritional indicators had a higher prognostic value in all indexes, especially GNRI. The C-index (95% confidence interval) of the nomograms for predicting the survival probability of patients who received ICIs were 0.801 (0.746-0.877) and 0.823 (0.761-0.898) for PFS and overall OS, respectively, which also showed high accuracy. In conclusion, the present study demonstrated that PNI, GNRI, NRI, SII, SIRI and ALI were all related to the efficacy of ICIs in HCC and could serve as non-invasive biomarkers for ICI treatment effectiveness. Moreover, compared with inflammatory markers, nutritional markers had greater predictive ability, with GNRI being the biomarker with the best prognostic value.

Hypoxia-inducible factor orchestrates adenosine metabolism to promote liver cancer development

Hypoxia-induced adenosine creates an immunosuppressive tumor microenvironment (TME) and dampens the efficacy of immune checkpoint inhibitors (ICIs). We found that hypoxia-inducible factor 1 (HIF-1) orchestrates adenosine efflux through two steps in hepatocellular carcinoma (HCC). First, HIF-1 activates transcriptional repressor MXI1, which inhibits adenosine kinase (ADK), resulting in the failure of adenosine phosphorylation to adenosine monophosphate. This leads to adenosine accumulation in hypoxic cancer cells. Second, HIF-1 transcriptionally activates equilibrative nucleoside transporter 4, pumping adenosine into the interstitial space of HCC, elevating extracellular adenosine levels. Multiple in vitro assays demonstrated the immunosuppressive role of adenosine on T cells and myeloid cells. Knockout of ADK in vivo skewed intratumoral immune cells to protumorigenic and promoted tumor progression. Therapeutically, combination treatment of adenosine receptor antagonists and anti-PD-1 prolonged survival of HCC-bearing mice. We illustrated the dual role of hypoxia in establishing an adenosine-mediated immunosuppressive TME and offered a potential therapeutic approach that synergizes with ICIs in HCC.

Beyond CPS for PD-L1 scoring: Genetic alterations that impact efficacy of immunotherapy in hepatocellular carcinoma (HCC).

592 Background: Tumor-agnostic approvals of immune checkpoint inhibitors (ICI) include deficient mismatch repair/microsatellite instability high (dMMR/MSI-H) and high tumor mutational burden (TMB) while in cancer like metastatic gastroesophageal cancers, ICI use has been predicated on PD-L1 expression. ICI are increasingly used for metastatic HCC, but without required markers. We aimed to examine the genomic landscape of HCC in context of PD-L1 expression, and to determine clinical responses to ICI in this setting. Methods: Next-generation sequencing of DNA (592 or WES) and RNA (WTS) was tested at Caris Life Sciences (Phoenix, AZ). PD-L1 expression was tested by IHC (SP142) and compared as high (2+,5%), low (1-2,1%) and negative (0). dMMR/MSI-H was tested by IHC/NGS and TMB-High was defined as ³10 mutations/MB. QuantiSEQ was used to estimate the tumor microenvironment. X2/Fisher-Exact were used and significance was determined as P-value adjusted for multiple comparison ( Q &lt; 0.05). Real-world overall survival (rwOS) was obtained from insurance claims and calculated from tissue collection to last contact; time-on-treatment (TOT) was calculated from start to finish of ICI treatments. Results: Overall, 17.7% of HCC expressed PD-L1 by IHC; 79/1306 (6.1%) had high expression. The overall prevalence of dMMR/MSI-H was 0.2%; TMB was high in 5.1%. PD-L1 expression was not associated with MSI-H or high TMB. When comparing tumors that are PD-L1 high vs. negative vs. low, expression of several immuno-oncologic (IO) markers LAG3 (median TPM: 2.4, 0.8, 0.5), CTLA-4 (2.9, 1.2, 0.5), IDO1 (4.2, 1.3, 0.6) and others, as well as T-cell inflamed and IFNg scores all decreased significantly with PD-L1 (all q&lt;0.05), similar trends were seen with B cells, M1 macrophages, CD8+ T cells and T regs while opposite differences seen in NK cells (q&lt;0.05). Additionally, when PDL1-high tumors were compared to PDL1-negative, mutations in CTNNB1 trended lower (21% vs 35%) while amplifications of KRAS (4% vs 0%), PDCD1LG2 (4% vs 0%) and mutations in HNF1A (3% vs 0%), HOXB13 (6% vs 0%), STK11 (5% vs 0%) trended higher; when PDL1-low were compared to PDL1-negative, mutations in TP53 (45% vs 32%), ELF3 (3% vs 0%), TSC2 (6% vs 2%) and PIK3CA (5% vs 1%) and amplifications in BCL9 (2% vs 0%) and CCNE1 (2% vs 0%) trended higher. When investigating clinical outcome of a cohort of 908 HCC tumors, PD-L1 expression had no effect on prognosis, and was not associated with differences in TOT of ICI in HCC. Conclusions: Prevalence of dMMR/MSI-H and TMB-H is very low in HCC. PD-L1 is only expressed in &lt;20%. Even with a finding of strong association of expression of several established IO biomarkers with PD-L1 expression, it’s still not predictive of response to ICI. New biomarkers or molecular signatures need to be identified and validated to objectively identify HCC patients most likely to benefit from ICI treatment.

Efficacy and safety associated with immune checkpoint inhibitors in unresectable hepatocellular carcinoma: A re-analysis of a meta-analysis.

We identified analytic limitations in a recent meta-analysis and re-examined the efficacy and safety associated with immune checkpoint inhibitors (ICIs) in unresectable hepatocellular carcinoma (HCC) compared with standard therapies. Our findings mostly contradict conclusions from the previous study, suggesting the need for continuing the investigation of ICIs in HCC with additional clinical evidence.

MicroRNAs act as a predictor in liver cancer immunotherapy

Hepatocellular carcinoma (HCC) is the most common type of liver cancer. Unfortunately, it is frequently diagnosed in advanced stages, limiting the available treatment options. Immune checkpoint inhibitors (ICIs) have shown promise in treating HCC, although their effectiveness varies among patients and can result in undesirable side effects. To enhance treatment outcomes and ensure patient safety, close monitoring and early intervention for side effects are necessary. Consequently, the selection of biomarkers that can predict the response to ICIs in HCC becomes crucial. MicroRNAs, which play a vital role in regulating gene expression in HCC, have emerged as potential biomarkers for predicting treatment response. Some microRNAs have been found to affect ICIs such as CTLA-4 and PD-L1, which are the targets of checkpoint inhibitor therapy. By identifying specific microRNAs that can forecast the response to ICIs, healthcare providers can personalize treatment plans for HCC patients. This tailored approach optimizes resource utilization and minimizes the risk of adverse side effects. Ultimately, this personalized strategy can improve treatment outcomes and enhance the quality of life for individuals with HCC. Thus, the selection of microRNAs capable of predicting the response to ICIs in HCC treatment holds significant importance. It has the potential to enhance patient response rates, decrease adverse effects, and optimize the utilization of healthcare resources.

Using mouse liver cancer models based on somatic genome editing to predict immune checkpoint inhibitor responses

Tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) are the only two classes of FDA-approved drugs for individuals with advanced hepatocellular carcinoma (HCC). While TKIs confer only modest survival benefits, ICIs have been associated with remarkable outcomes but only in the minority of patients who respond. Understanding the mechanisms that determine the efficacy of ICIs in HCC will help to stratify patients likely to respond to ICIs. This study aims to elucidate how genetic composition and specific oncogenic pathways regulate the immune composition of HCC, which directly affects response to ICIs. A collection of mouse HCCs with genotypes that closely simulate the genetic composition found in human HCCs were established using genome-editing approaches involving the delivery of transposon and CRISPR-Cas9 systems by hydrodynamic tail vein injection. Mouse HCC tumors were analyzed by RNA-sequencing while tumor-infiltrating T cells were analyzed by flow cytometry and single-cell RNA-sequencing. Based on the CD8+ T cell-infiltration level, we characterized tumors with different genotypes into cold and hot tumors. Anti-PD-1 treatment had no effect in cold tumors but was greatly effective in hot tumors. As proof-of-concept, a cold tumor (Trp53KO/MYCOE) and a hot tumor (Keap1KO/MYCOE) were further characterized. Tumor-infiltrating CD8+ T cells from Keap1KO/MYCOE HCCs expressed higher levels of proinflammatory chemokines and exhibited enrichment of a progenitor exhausted CD8+ T-cell phenotype compared to those in Trp53KO/MYCOE HCCs. The TKI sorafenib sensitized Trp53KO/MYCOE HCCs to anti-PD-1 treatment. Single anti-PD-1 treatment appears to be effective in HCCs with genetic mutations driving hot tumors, while combined anti-PD-1 and sorafenib treatment may be more appropriate in HCCs with genetic mutations driving cold tumors. Genetic alterations of different driver genes in mouse liver cancers are associated with tumor-infiltrating CD8+ T cells and anti-PD-1 response. Mouse HCCs with different genetic compositions can be grouped into hot and cold tumors based on the level of tumor-infiltrating CD8+ T cells. This study provides proof-of-concept evidence to show that hot tumors are responsive to anti-PD-1 treatment while cold tumors are more suitable for combined treatment with anti-PD-1 and sorafenib. Our study might help to guide the design of patient stratification systems for single or combined treatments involving anti-PD-1.

Identification of chromatin organization-related gene signature for hepatocellular carcinoma prognosis and predicting immunotherapy response

BackgroundChromatin organization is associated with tumorigenesis; however, information on its role in hepatocellular carcinoma (HCC) is limited. Moreover, although immune checkpoint inhibitors (ICIs) have proven effective against HCC, the optimal index remains unknown. In this study, we aimed to construct a chromatin organization-related gene signature (CORGS) for prognosis and predicting response to ICIs in HCC. MethodsHCC-related data were obtained from The Cancer Genome Atlas (TCGA) and International Cancer Genome Construction (ICGC). Chromatin organization-related genes (CORGs) were retrieved from Gene Set Enrichment Analysis. Differentially expressed genes (DEGs) and prognostic genes were then applied to select candidate genes using advanced statistical methods, including learning vector quantization, random forest, and lasso regression. Subsequently, the CORGS was established based on chromatin organization-related hub genes using multivariate Cox regression analysis, evaluated with Kaplan-Meier survival curves, and verified in 64 samples of HCC patients from Fujian Provincial Hospital (FPH) via quantitative PCR. Subsequently, functional enrichment analysis, tumor somatic mutation analysis, and tumor immune analysis were performed to evaluate the potential value of the CORGS. ResultsThree hundred and thirty-nine CORGs were identified as DEGs, and 186 were associated with HCC prognosis (all P < 0.05). Four intersection genes were selected to establish the CORGS using TCGA cohort, which was found to serve as an independent risk factor for HCC patients. CORGS was then validated in an ICGC cohort. In addition, CORGS reliability was verified in 64 samples from HCC patients and 26 adjacent non-tumorous tissues, collected from the FPH. The CORGS was also associated with tumor immune microenvironment characteristics and ICI response. Moreover, data from “IMvigor 210” revealed that more patients in the low CORGS group responded to atezolizumab compared to high CORGS patients (P < 0.05). Finally, a nomogram of tumor characteristics and the CORGS was established, exhibiting superior discrimination and calibration compared to the current staging system and published models. ConclusionsCORGS may serve as an effective predictive biomarker for HCC as well as a potential index of the tumor immune microenvironment and ICI response.

How Immunotherapy Has Changed the Continuum of Care in Hepatocellular Carcinoma.

Simple SummaryHCC is a very aggressive disease and patients diagnosed in an advanced/metastatic setting obtain poor survival outcomes with standard treatments. In recent years, the introduction of immunotherapy strategies, such as immune checkpoint inhibitors as single agents and in combination with already approved local and systemic treatments, has strongly changed the therapeutic landscape of HCC. Soon, the discovery of novel potential immune targets, together with the understanding of potential biomarkers of resistance, will help to better define novel treatment opportunities for patients with HCC.Hepatocellular carcinoma (HCC) is one of the leading causes of death worldwide. The use of local treatment, such as surgical resection, liver transplant, and local ablation, has improved the survival of patients with HCC detected at an early stage. Until recently, the treatment of patients with metastatic disease was limited to the use of the multikinase inhibitor (MKI) sorafenib with a marginal effect on survival outcome. New target approaches, such as the oral MKI lenvatinib in first-line treatment and regorafenib, ramucirumab, and cabozantinib in later lines of therapy, have demonstrated efficacy in patients with preserved liver function (Child–Pugh class A) and good performance status. On the other hand, the implementation of immune checkpoint inhibitors directed against PD-1 (nivolumab and pembrolizumab), PD-L1 (atezolizumab), and anti-CTLA4 (ipilimumab) in the management of advanced HCC has strongly changed the continuum of care of HCC. Future research should include the evaluation of molecular biomarkers that can help patient selection and provide new insight on potential combined approaches. In this review, we provide an overview of the clinical evidence of the use of immune checkpoint inhibitors in HCC, and discuss how immunotherapy has been implemented into the continuum of HCC care.

DNA Damage Repair Status Predicts Opposite Clinical Prognosis Immunotherapy and Non-Immunotherapy in Hepatocellular Carcinoma.

Immune checkpoint inhibitors(ICIs) that activate tumor-specific immune responses bring new hope for the treatment of hepatocellular carcinoma(HCC). However, there are still some problems, such as uncertain curative effects and low objective response rates, which limit the curative effect of immunotherapy. Therefore, it is an urgent problem to guide the use of ICIs in HCC based on molecular typing. We downloaded the The Cancer Genome Atlas-Liver hepatocellular carcinoma(TCGA-LIHC) and Mongolian-LIHC cohort. Unsupervised clustering was applied to the highly variable data regarding expression of DNA damage repair(DDR). The CIBERSORT was used to evaluate the proportions of immune cells. The connectivity map(CMap) and pRRophetic algorithms were used to predict the drug sensitivity. There were significant differences in DDR molecular subclasses in HCC(DDR1 and DDR2), and DDR1 patients had low expression of DDR-related genes, while DDR2 patients had high expression of DDR-related genes. Of the patients who received traditional treatment, DDR2 patients had significantly worse overall survival(OS) than DDR1 patients. In contrast, of the patients who received ICIs, DDR2 patients had significantly prolonged OS compared with DDR1 patients. Of the patients who received traditional treatment, patients with high DDR scores had worse OS than those with low DDR scores. However, the survival of patients with high DDR scores after receiving ICIs was significantly higher than that of patients with low DDR scores. The DDR scores of patients in the DDR2 group were significantly higher than those of patients in the DDR1 group. The tumor microenvironment(TME) of DDR2 patients was highly infiltrated by activated immune cells, immune checkpoint molecules and proinflammatory molecules and antigen presentation-related molecules. In this study, HCC patients were divided into the DDR1 and DDR2 group. Moreover, DDR status may serve as a potential biomarker to predict opposite clinical prognosis immunotherapy and non-immunotherapy in HCC.

Risk Signature Related to Immunotherapy Reaction of Hepatocellular Carcinoma Based on the Immune-Related Genes Associated With CD8+ T Cell Infiltration.

Background: Hepatocellular carcinoma (HCC) is the most common histological type of liver cancer, with an unsatisfactory long-term survival rate. Despite immune checkpoint inhibitors for HCC have got glories in recent clinical trials, the relatively low response rate is still a thorny problem. Therefore, there is an urgent need to screen biomarkers of HCC to predict the prognosis and efficacy of immunotherapy. Methods: Gene expression profiles of HCC were retrieved from TCGA, GEO, and ICGC databases while the immune-related genes (IRGs) were retrieved from the ImmPort database. CIBERSORT and WGCNA algorithms were combined to identify the gene module most related to CD8+ T cells in the GEO cohort. Subsequently, the genes in hub modules were subjected to univariate, LASSO, and multivariate Cox regression analyses in the TCGA cohort to develop a risk signature. Afterward, the accuracy of the risk signature was validated by the ICGC cohort, and its relationships with CD8+ T cell infiltration and PDL1 expression were explored. Results: Nine IRGs were finally incorporated into a risk signature. Patients in the high-risk group had a poorer prognosis than those in the low-risk group. Confirmed by TCGA and ICGC cohorts, the risk signature possessed a relatively high accuracy. Additionally, the risk signature was demonstrated as an independent prognostic factor and closely related to the CD8+ T cell infiltration and PDL1 expression. Conclusion: A risk signature was constructed to predict the prognosis of HCC patients and detect patients who may have a higher positive response rate to immune checkpoint inhibitors.

Adverse Effects of Immune-Checkpoint Inhibitors in Hepatocellular Carcinoma.

Immune-modulatory therapy, especially with immune-checkpoint inhibitors (ICIs), has reshaped cancer therapeutics. Immunotherapy is relatively a novel approach that can effectively delay the progression of aggressive tumors and inhibit tumor recurrence and metastasis in many different tumor types. In the past years, ICIs have shown a sustained response and promising long-term survival in patients with advanced hepatocellular carcinoma (HCC). Nevertheless, ICI therapy can unbalance the immune system and result in a wide range of immune-related adverse events (irAEs), which are generally manageable but occasionally lead to a fatal outcome. HCC generally develops in the context of liver cirrhosis which is typically caused by viral hepatitis and non-alcoholic steatohepatitis. These underlying diseases may cause symptoms that overlap with irAEs and lead to consequences such as late recognition, inadequate work-up, and inappropriate treatment. Owing to the growing use of immunotherapy in HCC, it is necessary for clinicians to strengthen their understanding of the frequency, clinical features, and management of irAEs. This review focuses on the common toxicities associated with ICI therapy in patients with HCC and summarizes therapeutic strategies that can be used to monitor and manage such toxicities.

PKM2 Drives Hepatocellular Carcinoma Progression by Inducing Immunosuppressive Microenvironment.

Background and AimsPyruvate kinase M2 (PKM2) is an essential regulator of the Warburg effect, but its biological function promoting immune escape of hepatocellular carcinoma (HCC) is unclear.MethodsGEPIA web tool and immunohistochemistry (IHC) analysis were employed to evaluate the clinical relevance of PKM2 in HCC patients. Both in vitro CCK-8, colony formation, and transwell assays, and in vivo xenografts were performed to evaluate the malignancy of HCC cells. PKM2 and PD-L1 levels were examined by Western blot, qRT-PCR, and IHC. The role of PKM2 on in vivo immune response was also investigated.ResultsPKM2 was significantly upregulated in HCC and associated with a poor prognosis of HCC patients. Knockdown of PKM2 inhibited in vitro proliferation, migration, and invasion of HCC cells, as well as in vivo tumor growth. Strikingly, PKM2 showed a strong correlation with the expression of immune inhibitory cytokines and lymphocyte infiltration in HCC. The overexpression of PKM2 sensitized HCC to immune checkpoint blockade, which enhanced IFN-γ positive CD8 T cells in HCC mice models.ConclusionPKM2 might be a predictor and a potential therapeutic target for immune checkpoint inhibitors in HCC.

Immune Checkpoint Inhibitors in Hepatocellular Carcinoma: Current Status and Novel Perspectives.

Simple SummaryImmune checkpoint inhibitors represent a promising treatment choice in many kind of tumours, including hepatocellular carcinoma (HCC). In this review, we provide an overview of the role of these new agents in the management of HCC according to the Barcelona staging system, alongside with a critical evaluation of the current status and future directions. Several clinical trials are focusing on the use of immunotherapy in HCC, alone or in combinations with antiangiogenetic agents as well as local treatment. However, the majority of those trials are still ongoing and, until now, only a few combinations were approved in the clinical practice from the regulatory authorities. Additionally, decisions about the choice of the right sequence of treatments in HCC patients in the light of the “continuum of care” principles, is still hard. In fact, it requires careful consideration in a multidisciplinary context in order to ensure a tailored treatment for each patient. Immune checkpoint inhibitors (ICIs) represent a promising treatment for many kinds of cancers, including hepatocellular carcinoma (HCC). The rationale for using ICIs in HCC is based on the immunogenic background of hepatitis and cirrhosis and on the observation of high programmed death-ligand 1 (PD-L1) expression and tumor-infiltrating lymphocytes in this cancer. Promising data from phase I/II studies in advanced HCC, showing durable objective response rates (~20% in first- and second-line settings) and good safety profile, have led to phase III studies with ICIs as single agents or in combination therapy, both in first and second line setting. While the activity of immunotherapy agents as single agents seems to be limited to an “ill-defined” small subset of patients, the combination of the anti PD-L1 atezolizumab and anti-vascular endothelial growth factor bevacizumab revealed a benefit in the outcomes when compared to sorafenib in the first line. In addition, the activity and efficacy of the combinations between anti-PD-1/anti-PD-L1 antibody and other ICIs, tyrosine kinase inhibitors, or surgical and locoregional therapies, has also been investigated in clinical trials. In this review, we provide an overview of the role of ICIs in the management of HCC with a critical evaluation of the current status and future directions.

Immunotherapy in Hepatocellular Cancer Patients with Mild to Severe Liver Dysfunction: Adjunctive Role of the ALBI Grade

Immune checkpoint inhibitors (ICI) have shown positive results in patients with hepatocellular carcinoma (HCC). As liver function contributes to prognosis, its precise assessment is necessary for the safe prescribing and clinical development of ICI in HCC. We tested the accuracy of the albumin-bilirubin (ALBI) grade as an alternative prognostic biomarker to the Child-Turcotte-Pugh (CTP). In a prospectively maintained multi-centre dataset of HCC patients, we assessed safety and efficacy of ICI across varying levels of liver dysfunction described by CTP (A to C) and ALBI grade and evaluated uni- and multi-variable predictors of overall (OS) and post-immunotherapy survival (PIOS). We studied 341 patients treated with programmed-death pathway inhibitors (n = 290, 85%). Pre-treatment ALBI independently predicted for OS, with median OS of 22.5, 9.6, and 4.6 months across grades (p < 0.001). ALBI was superior to CTP in predicting 90-days mortality with area under the curve values of 0.65 (95% CI 0.57–0.74) versus 0.63 (95% CI 0.54–0.72). ALBI grade at ICI cessation independently predicted for PIOS (p < 0.001). Following adjustment for ICI regimen, neither ALBI nor CTP predicted for overall response rates or treatment-emerging adverse events (p > 0.05). ALBI grade identifies a subset of patients with prolonged survival prior to and after ICI therapy, lending itself as an optimal stratifying biomarker to optimise sequencing of systemic therapies in advanced HCC.