Rationale of Immunotherapy in Hepatocellular Carcinoma and Its Potential Biomarkers

Abstract

Hepatocellular carcinoma (HCC), the most common type of liver cancer, is derived mostly from a background of chronic inflammation. Multiple immunotherapeutic strategies have been evaluated in HCC, with some degree of success, particularly with immune checkpoint blockade (ICB). Despite the initial enthusiasm, treatment benefit is only appreciated in a modest proportion of patients (response rate to single agent ~20%). Therapy-induced immune-related adverse events (irAEs) and economic impact are pertinent considerations with ICB. It is imperative that a deeper understanding of its mechanisms of action either as monotherapy or in combination with other therapeutic agents is needed. We herein discuss the latest developments in the immunotherapeutic approaches for HCC, the potential predictive biomarkers and the rationale for combination therapies. We also outline promising future immunotherapeutic strategies for HCC patients.

<p>Emerging Role of Immunotherapy for Colorectal Cancer with Liver Metastasis</p>

“…In recent years, immunotherapy has achieved a certain degree of success in the treatment of advanced solid tumors. 13 The purpose of immunotherapy is to enhance the anti-tumor effect of patient's own immune system by augmenting the innate immunity and antitumor function of T cells, and by targeting immunosuppressive tumorassociated macrophages. 14 Immunotherapies include immune checkpoint inhibitors (ICIs); cancer vaccines; and other biotherapeutics such as chimeric antigen receptor (CAR) T cells.…”

“…64 Unlike conventional cancer therapies, immunotherapy potentiates the patient's immune system or modulates the TME instead of directly targeting tumor cells. 13 Malignant cells can escape the antitumor immunity; therefore, the major aim of immunotherapy, such as ICIs, is to block the immune evasion mechanisms of tumor cells, 65 thereby suppressing tumor progression, relapse, and metastasis.…”

Mitochondrial uncoupling and the disruption of the metabolic network in hepatocellular carcinoma

“…In recent years, sorafenib, a known multi-kinase inhibitor, became the first-line treatment for advanced-stage HCC, but unfortunately provided limited improvement in patient survival [2]. Although other kinase and immune checkpoint inhibitors are now considered second-line options, the data supporting improved outcomes relative to sorafinib is not yet compelling [3,4].…”

“…Because to the lack of treatment options in advanced cases, our group and others have developed strategies using small-molecules targeting different pathways with or without immunotherapy for late stages in pre-clinical or clinical studies [3][4][5][6][7][8][9][10][11]. The Wnt/βcatenin pathway is critical for HCC cell proliferation, progression and stemness, and this pathway is aberrant in 30-50% of the HCC tumors [12][13][14][15][16].…”

Identification of a Five-Immune Gene Model as an Independent Prognostic Factor in Hepatocellular Carcinoma

“…A variety of strategies, including cancer vaccines, adoptive cellular therapy, and immune checkpoint blockade (ICB), have been explored. ICB has got promising outcomes in HCC [6,7]. Besides, several immune checkpoint inhibitors, such as anti-PD-L1, anti-CTLA-4, and anti-PD-1 antibodies, have also displayed potential therapeutic effects on HCC [8,9], and these immune checkpoints have been reported to participate in the induction and maintenance of immune tolerance in HCC [10,11].…”