Cellular and molecular targets for the immunotherapy of hepatocellular carcinoma

Abstract

Liver cancer is the sixth most common cancer worldwide and 3rd most common cause of cancer-related death. Hepatocellular carcinoma (HCC) represents more than 90% of primary liver cancer and is a major public health problem. Due to the advanced stages of HCC at the time of diagnosis, utilizing the conventional treatment for solid tumors frequently ends with treatment failure, recurrence, or poor survival. HCC is highly refractory to chemotherapy and other systemic treatments, and locoregional therapies or selective internal radiation therapies are largely palliative. Considering how the pathogenesis of HCC often induces an immunosuppressed state which is further amplified by post-treatment recurrence and reactivation, immunostimulation provides a potential novel approach for the treatment of HCC. Immune response(s) of the body may be potentiated by immunomodulation of various effector cells such as B-cells, T-cells, Treg cells, natural killer cells, dendritic cells, cytotoxic T-lymphocytes, and other antigen-presenting cells; cellular components such as genes and microRNA; and molecules such as proteins, proteoglycans, surface receptors, chemokines, and cytokines. Targeting these effectors individually has helped in the development of newer therapeutic approaches; however, combinational therapies targeting multi-faceted biomarkers have yielded better results. Still, there is a need for further research to develop novel therapeutic strategies which may act as either complementary or an alternative treatment to the standard therapy protocols of HCC. This review focuses on potential cellular and molecular targets, as well as the role of virotherapy and combinational therapy in the treatment of HCC.

Liver, Tumor and Viral Hepatitis: Key Players in the Complex Balance Between Tolerance and Immune Activation

“…Increased tumorspecific cytotoxicity has indeed been detected after this type of therapies (124)(125)(126). The potential side effect of this treatment is that the presence of PD-L1 on most of APCs in the liver could actually inhibit the tumor-specific T cell response (127) so one obvious measure would be to combine ablation therapy with PD-1 blockade treatment (128,129). This is currently tested in various clinical trials.…”

“…It is logical to assume that targeting the immune cells in the liver, reverting what cause their anergic state, may offer a solution for cancer treatment. Several immunotherapy trials have been conducted for HCC with cell therapy (LAK and TIL), cytokines and check-point inhibitors, dendritic cells vaccines and combinations of the above (129). The outcomes of these trials are promising but still not enough to offer a complete remission for HCC.…”

Stereotactic Body Radiotherapy: Does It Have a Role in Management of Hepatocellular Carcinoma?

“…Unlike certain other malignancies, HCC cells do not appear to be inherently immunogenic. However, recent papers that studied checkpoint inhibitors for HCC demonstrated promising results, 52 53 and more phase I and II clinical studies are underway to investigate the effects of various immune checkpoint inhibitors, including cytotoxic T-lymphocyte-associated protein-4 inhibitors and anti-programmed death-1 (anti-PD-1) antibody. Nevertheless, modest response rates have indicated that the efficacy of these checkpoint inhibitors appears to be insufficient.…”

Unconventional Approaches to Modulating the Immunogenicity of Tumor Cells

“…And, several pan-HDAC inhibitors, such as sodium valproate, etinostat, panobinostat, and vorinostat, have all been shown in vivo to enhance the antitumor efficacy of checkpoint inhibitory antibodies, as well as promote activated T cell infiltration into the tumors (Booth, Roberts, Poklepovic, & Dent, 2017; Booth, Roberts, Poklepovic, Kirkwood, & Dent, 2017; Christiansen et al, 2011; Gameiro, Malamas, Tsang, Ferrone, & Hodge, 2016; Hornig, Heppt, Graf, Ruzicka, & Berking, 2016; Kroesen et al, 2016; Vo et al, 2009; West & Johnstone, 2014; West et al, 2013). Tumor types tested in these studies are diverse and include melanoma, breast, colorectal, glioblastoma, and hepatoma (Chae, Wang, Nimeiri, Kalyan, & Giles, 2017; Huang et al, 2017; Keller, Zhang, Li, Schaider, & Wells, 2017; Monnot & Romero, 2017; Rai et al, 2017). …”