Insights into an Immunotherapeutic Approach to Combat Multidrug Resistance in Hepatocellular Carcinoma

Abstract

Hepatocellular carcinoma (HCC) has emerged as one of the most lethal cancers worldwide because of its high refractoriness and multi-drug resistance to existing chemotherapies, which leads to poor patient survival. Novel pharmacological strategies to tackle HCC are based on oral multi-kinase inhibitors like sorafenib; however, the clinical use of the drug is restricted due to the limited survival rate and significant side effects, suggesting the existence of a primary or/and acquired drug-resistance mechanism. Because of this hurdle, HCC patients are forced through incomplete therapy. Although multiple approaches have been employed in parallel to overcome multidrug resistance (MDR), the results are varying with insignificant outcomes. In the past decade, cancer immunotherapy has emerged as a breakthrough approach and has played a critical role in HCC treatment. The liver is the main immune organ of the lymphatic system. Researchers utilize immunotherapy because immune evasion is considered a major reason for rapid HCC progression. Moreover, the immune response can be augmented and sustained, thus preventing cancer relapse over the post-treatment period. In this review, we provide detailed insights into the immunotherapeutic approaches to combat MDR by focusing on HCC, together with challenges in clinical translation.

Keywords: hepatocellular carcinoma; immunotherapy; multidrug resistance.

Figure 1

Anatomical organization and distribution of various immune cells in the liver. The sinusoidal endothelial cells of the liver in the sinusoidal lining directly interact with resident liver macrophages, KCs. The liver harbors varying proportions of lymphoid cells such as natural killer cells, natural killer T cells, γδT cells, and liver transiting or resident T cells.

Figure 2

Schematic representation of engineering TCR to target HCC tumor-specific antigens. T lymphocytes are isolated from the blood and genetically modified to express T-cell receptors, which can recognize a specific tumor-associated antigen and elicit cell-specific cytotoxicity. After expansion, these engineered T cells are injected into the patient.

Figure 3

(a) Active immune surveillance against tumor cells. APCs capture TAAs released from tumor cells because of necrosis to its surface through the MHC. The binding of TAA-linked APC to the specific TCR of CD8+ T cells leads to its activation of the effector T-cell phenotype and CTL. (b) Immune evasion strategies of tumor cells. Tumor cells escape from T cell-mediated anticancer immunosurveillance mainly via the inhibition of production and presentation of TAA, deficient expression of MHC-1, and expression of immune inhibitory surface proteins. (c) CAR-T cell therapy. T cells isolated from the patient’s blood were transduced with a CAR gene for modified antigen receptors that can specifically target a tumor-specific antigen and destroy it without the need of MHCs (unlike T cells) and immunization (unlike vaccine). The expanded and screened CART-T cells are reinjected into the patient. Structurally, CAR is made of an extracellular antigen-binding domain of a tumor-specific antibody connected to an intracellular domain comprising CD3 of TCR via a transmembrane hinge region. Structural modifications of the intracellular domain with a costimulatory domain of CD28 results in the formation of second-generation CARs, whereas third-generation CARs comprise two co-stimulatory domains.

Figure 4

Mechanism of action of PD-I immune checkpoint inhibitors. PD-1 is a protein present on the T-cell surface. The corresponding ligand of PD-1 is called PD-L1, which is overexpressed in cancer cells. The interaction PD-1 and PD-L1blocks the cytotoxic effect of T cells. Pembrolizumab, a PD-1 inhibitor, prevents the interaction of PD-1 with its corresponding ligand and elicits an immune reaction.

Figure 5

Mechanism of action of CTLA-4 immune checkpoint inhibitor. CTLA-4 can bind with the CD80/CD86 proteins, which are overexpressed in APC. This interaction blocks the cytotoxic effect of T cells by blocking the binding of T cells with the MHC protein present in cancer cells. Ipilimumab, an anti-CTLA-4 antibody, forestalls the interaction between CD80/CD86 and CTLA-4 and elicits an immune response.