Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death since most patients are diagnosed at advanced stage and the current systemic treatment options using molecular-targeted drugs remain unsatisfactory. However, the recent success of cancer immunotherapies has revolutionized the landscape of cancer therapy. Since HCC is characterized by metachronous multicentric occurrence, immunotherapies that induce systemic and durable responses could be an appealing treatment option. Despite the suppressive milieu of the liver and tumor immunosurveillance escape mechanisms, clinical studies of checkpoint inhibitors in patients with advanced HCC have yielded promising results. Here, we provide an update on recent advances in HCC immunotherapies. First, we describe the unique tolerogenic properties of hepatic immunity and its interaction with HCC and then review the status of already or nearly available immune checkpoint blockade-based therapies as well as other immunotherapy strategies at the preclinical or clinical trial stage.

Background: Combination therapy with anti-programmed death-ligand 1 monoclonal antibody atezolizumab plus anti-vascular endothelial growth factor agent bevacizumab (Atezo/Bev) was approved in 2020 as a first-line treatment for unresectable hepatocellular carcinoma (HCC). Atezo/Bev therapy is relatively well tolerated; however, factors that can predict its response have not yet been reported. Thus, we aimed to investigate whether the pretreatment neutrophil-to-lymphocyte ratio (NLR) could predict the therapeutic response in patients with HCC treated with Atezo/Bev therapy. Methods: We analyzed the course of 40 patients with HCC who received Atezo/Bev therapy at our hospital and attempted to identify pretreatment factors that could predict response by comparing those who achieved disease control with those who did not. Results: The pretreatment NLR value in patients who achieved disease control was significantly lower than that in patients with disease progression (2.47 vs. 4.48, p = 0.013). Using the optimal NLR cut-off value for predicting response (3.21) determined by receiver operating characteristic curve analysis, patients with NLR ≤ 3.21 had significantly better progression-free survival than those with NLR > 3.21 (p < 0.0001), although there were no significant differences in liver function or tumor-related background factors between the two groups. Conclusions: The pretreatment NLR value may be a useful predictor of response to Atezo/Bev therapy for HCC.

Risk factors and diagnostic biomarkers for nonalcoholic fatty liver disease-associated hepatocellular carcinoma: Current evidence and future perspectives

Lenvatinib was recently approved as a novel first-line molecular targeted agent (MTA) for treating hepatocellular carcinoma (HCC). The importance of relative dose intensity (RDI) has been shown in the treatment of various types of cancers. However, RDI may not accurately reflect the treatment intensity of lenvatinib, as it is the first oral MTA where the dose is based on the patient’s weight. We aimed to evaluate the utility of 2M-DBR (the delivered dose intensity/body surface area ratio at 60 days) by comparing the relationship between 2M-DBR, 2M-RDI (RDI at 60 days), and the therapeutic response. The therapeutic response to lenvatinib was evaluated in 45 patients who underwent computed tomography 8–12 weeks after treatment initiation. We also investigated the clinical factors associated with high 2M-DBR. The area under the receiver operating characteristic of 2M-DBR that predicts the response to lenvatinib was higher than that of 2M-RDI (0.8004 vs. 0.7778). Patients with high 2M-DBR achieved significantly better objective responses and disease control rates than those with low 2M-DBR (p < 0.0001 and 0.0008). Patients with high 2M-DBR experienced significantly longer progression-free survival (PFS) than those with low 2M-DBR (p = 0.0001), while there was no significant correlation between 2M-RDI levels and PFS (p = 0.2198). Patients who achieved higher levels of 2M-DBR had a significantly better modified ALBI grade (p = 0.0437), better CONUT score (p = 0.0222), and higher BTR (p = 0.0281). Multivariate analysis revealed that high 2M-DBR was the only significant factor associated with longer PFS. In conclusion, 2M-DBR could be an important factor that reflects treatment intensity and useful for predicting the response to lenvatinib against HCC, instead of 2M-RDI.

Hepatocellular carcinoma (HCC) is a major cause of cancer-related death worldwide. Although several targeted therapy agents are available for advanced HCC, their antitumor efficacy remains limited. As the complex genetic landscape of HCC would compromise the antitumor efficacy of targeted therapy, a deeper understanding of the genetic landscape of hepatocarcinogenesis is necessary. Recent comprehensive genetic analyses have revealed the driver genes of HCC, which accumulate during the multistage process of hepatocarcinogenesis, facilitating HCC genetic heterogeneity. In addition, as early genetic changes may represent key therapeutic targets, the genetic landscapes of early HCC and precancerous liver tissues have been characterized in recent years, in parallel with the advancement of next-generation sequencing analysis. In this review article, we first summarize the landscape of the liver cancer genome and its intratumor heterogeneity. We then introduce recent insight on early genetic alterations in hepatocarcinogenesis, especially those in early HCC and noncancerous liver tissues. Finally, we summarize the multistep accumulation of genetic aberrations throughout cancer progression and discuss the future perspective towards the clinical application of this genetic information.

Transarterial chemoembolization (TACE) is the recommended first-line treatment for intermediate-stage hepatocellular carcinoma (HCC). In patients who became refractory to TACE, a treatment switch to tyrosine kinase inhibitors (TKIs) needs to be considered. However, TACE could worsen liver function, thereby narrowing the time window for a switch to TKIs because TKIs are recommended for patients with Child-Pugh grade A (CP-A). We investigated the factors associated with CP grade deterioration after TACE. Among patients who underwent TACE, 125 patients with CP-A were enrolled. The cumulative CP grade deterioration rates were 20.3%, 27.1%, and 41.4% at six months, one year, and two years, respectively. Multivariate analysis revealed that factors associated with CP grade deterioration included high Mac-2 binding protein glycosylation isomer (M2BPGi) levels (>2.00 cut-off index) and beyond the up-to-seven criteria. The cumulative CP grade deterioration rates of patients with high M2BPGi and beyond the up-to-seven criteria were 50.6% and 59.2% at six months and one year, respectively, which were significantly higher than for those in any other groups. The combination of M2BPGi and up-to-seven criteria could be a surrogate marker for predicting CP grade deterioration after TACE. In patients with intermediate-stage HCC, elevated M2BPGi levels, and beyond the up-to-seven criteria, an early treatment switch to TKIs should be considered to improve their prognosis.