Angiogenesis and immune checkpoint inhibitors as therapies for hepatocellular carcinoma: current knowledge and future research directions

Abstract

Hepatocellular carcinoma (HCC) is the second deadliest cancer worldwide, due to its high incidence and poor prognosis. Frequent initial presentation at advanced stages along with impaired liver function limit the use of a broad therapeutic arsenal in patients with HCC. Although main HCC oncogenic drivers have been deciphered in recent years (TERT, TP53, CTNNB1 mutations, miR122 and CDKN2A silencing), therapeutic applications derived from this molecular knowledge are still limited. Given its high vascularization and immunogenicity, antiangiogenics and immune checkpoint inhibitors (ICI), respectively, are two therapeutic approaches that have shown efficacy in HCC. Depending on HCC immune profile, combinations of these therapies aim to modify the protumoral/antitumoral immune balance, and to reactivate and favor the intratumoral trafficking of cytotoxic T cells. Combination therapies involving antiangiogenics and ICI may be synergistic, because vascular endothelial growth factor A inhibition increases intratumoral infiltration and survival of cytotoxic T lymphocytes and decreases regulatory T lymphocyte recruitment, resulting in a more favorable immune microenvironment for ICI antitumoral activity. First results from clinical trials evaluating combinations of these therapies are encouraging with response rates never observed before in patients with HCC. A better understanding of the balance and interactions between protumoral and antitumoral immune cells will help to ensure the success of future therapeutic trials. Here, we present an overview of the current state of clinical development of antitumoral therapies in HCC and the biological rationale for their use. Moreover, translational studies on tumor tissue and blood, prior to and during treatment, will help to identify biomarkers and immune signatures with predictive value for both clinical outcome and response to combination therapies.

SOD3 boosts T cell infiltration by normalizing the tumor endothelium and inducing laminin-α4

“…Clinical evidence suggests that anti-VEGF agents synergize with immune checkpoint inhibitors to improve disease control and overall survival in different cancer types, an effect associated with larger numbers of effector T cells in the TME. 4 Although an increase in TIL might be linked to transient normalization of the tumor vasculature, VEGF blockade can also create an immunodominant TME by impeding VEGF immunosuppressive activities. 4 We reported that perivascular SOD3 triggers a program that simultaneously induces vascular normalization and T cell infiltration, thus linking these two processes unequivocally.…”

“…4 Although an increase in TIL might be linked to transient normalization of the tumor vasculature, VEGF blockade can also create an immunodominant TME by impeding VEGF immunosuppressive activities. 4 We reported that perivascular SOD3 triggers a program that simultaneously induces vascular normalization and T cell infiltration, thus linking these two processes unequivocally. 5,6 The anti-oxidant enzyme SOD3 is usually downregulated in tumors, which suggests that its loss is advantageous for cancer progression.…”

Interim results from ongoing Phase III placebo-controlled, randomized trial of hepcortespenlisimut-L for advanced hepatocellular carcinoma indication

“…Recently, a study was published in Nature by Alspach et al [19] , in which they gave more weight to the role of helper CD4 lymphocytes in immuno-oncology over the usual culprit, i.e., CD8 killer cells. Whether V5 more affects CD4 rather than CD8 cells remains to be established; it is likely that both subpopulations are required, and that other subsets of immune cells are also critically involved [20,21] .…”

Liver-Targeting Class I Selective Histone Deacetylase Inhibitors Potently Suppress Hepatocellular Tumor Growth as Standalone Agents

“…Blockade of immune checkpoints (PD-1 alone or with CTLA-4) has also become an option recently, but the vast majority of patients (~70%) still do not respond to immunotherapy, even when combined with antiangiogenic drugs. Therefore, there is a clear need for more efficacious strategies for HCC treatment [9].…”