Oncogenic Signal and Tumor Microenvironment in Hepatocellular Carcinoma

Abstract

During tumor development, several immunosuppressive molecules are released from cancer cells and contribute to the establishment of immunosuppressive tumor environment. In tumor tissues, cytokines, chemokines, growth factors, and metabolites are present and could counter the effects of immune checkpoint inhibitors. From this point of view, monotherapy of anti-PD-1/PD-L1 antibody might not be enough to exert a sufficient antitumor effect; additional blockade of immunosuppressive molecules in tumor microenvironment could enhance the antitumor effect of anti-PD-1/PD-L1 antibody. Importantly, the production of immunosuppressive molecules in cancer cells is attributed to the activation of cellular signaling through genetic and epigenetic alterations and environmental stimulation, such as inflammation and hypoxia. In this review, we focus on the establishment of immunosuppressive microenvironment of hepatocellular carcinoma in the context of activation of oncogenic signals, and discuss how the immunosuppressive condition could be overcome using tyrosine kinase inhibitors.

Transforming Growth Factor‐β and Axl Induce CXCL5 and Neutrophil Recruitment in Hepatocellular Carcinoma

“…Chronic inflammation caused by these conditions leads to cell death, compensatory liver regeneration, and activation of nonparenchymal cells that promotes liver fibrosis and tumorigenesis . Alterations in the immune response involve the infiltration of adaptive and innate immune cells, producing a pathological milieu composed of multiple extracellular matrix proteins, growth factors, and chemokines that can form a protumorigenic stroma . It has been proposed that neutrophil infiltration is prognostic in several human cancers, including HCC .…”

Immune checkpoint blockade for the treatment of human hepatocellular carcinoma

“…In mouse model, targeted inhibition of IL‐6 could reportedly enhance the efficacy of anti‐PD‐L1 antibody, overcoming anti‐PD‐L1 resistance in HCC . A combined blockade using extracellular signal‐regulated kinase inhibition and anti‐PD‐L1 antibody should have a synergistic effect on tumor regression; thus, TKIs might enhance the effect of immune checkpoint inhibitors by altering the immune microenvironment of HCC …”

“…Sorafenib and regorafenib are available in the clinical setting for the treatment of advanced HCC; lenvatinib and cabozantinib have also shown a survival benefit . Given the fact that these agents could collectively block the signaling from various growth factors and affect immune effectors and the vasculature, the combination of TKIs and immune checkpoint inhibitors could reactivate the immune response to HCC . Several early phase studies are currently underway to explore the safety and tolerability of TKIs such as sorafenib (NCT03211416, NCT01658878, and NCT02988440), lenvatinib (NCT03418922 and NCT03006926), cabozantinib (NCT03299946 and NCT01658878), axitinib (NCT03289533), capmatinib (NCT02795429), and FGFR4 inhibitor (NCT02325739) in combination with immune checkpoint inhibitors (Table ).…”

“…58 A combined blockade using extracellular signalregulated kinase inhibition and anti-PD-L1 antibody should have a synergistic effect on tumor regression; thus, TKIs might enhance the effect of immune checkpoint inhibitors by altering the immune microenvironment of HCC. 59,60 Sorafenib and regorafenib are available in the clinical setting for the treatment of advanced HCC; lenvatinib and cabozantinib have also shown a survival benefit. 4,7,8 Given the fact that these agents could collectively block the signaling from various growth factors and affect immune effectors and the vasculature, the combination of TKIs and immune checkpoint inhibitors could reactivate the immune response to HCC.…”

New Paradigm in Gastrointestinal Cancer Treatment

“…Nishida and Kudo [38] described activation of oncogenic signaling and tumor immunosuppressive microenvironment in HCC. They stated that vascular endothelial growth factor (VEGF) induces myeloid-derived suppressor cell accumulation, inhibit maturation of dendritic cells, and induce Treg cells.…”