Advances in Immunotherapy for Hepatocellular Carcinoma

Abstract

Immune checkpoint inhibitors (ICIs) aim to induce immune responses against tumors and are less likely to develop drug resistance than molecularly targeted drugs. In addition, they are characterized by a long-lasting antitumor effect. However, since its effectiveness depends on the tumor's immune environment, it is essential to understand the immune environment of hepatocellular carcinoma to select ICI therapeutic indications and develop biomarkers. A network of diverse cellular and humoral factors establishes cancer immunity. By analyzing individual cases and classifying them from the viewpoint of tumor immunity, attempts have been made to select the optimal therapeutic drug for immunotherapy, including ICIs. ICI treatment is discussed from the viewpoints of immune subclass of HCC, Wnt/β-catenin mutation, immunotherapy in NASH-related HCC, the mechanism of HPD onset, and HBV reactivation.

Keywords: hepatocellular carcinoma; immune checkpoint inhibitors; tumor immune environment.

Figure 1

New immune subclass (modified quotation from [17]). A new immune-like subclass was proposed as a subclass of the inflamed class. While having similar immunological characteristics to the immune active/immune exhausted subclass, there are differences in molecular characteristics.

Figure 2

Duality of Wnt/β-catenin mutation (modified from [18]). Wnt/β-catenin mutations in HCC are divided into favorable and unfavorable phenotypes. HCC-specifically expressed tumor suppressor gene HNF4α is a target gene of Wnt/β-catenin signaling.

Figure 3

Mechanism of suppression of tumor infiltration of CD8-positive T cells by VEGF. In the cancer immune cycle, VEGF prevents infiltration of CD8-positive T cells flowing in the blood into the tumor. The main factors are that VEGF induces FAS ligand and causes CTL to undergo apoptosis, and that by reducing adhesion factors such as ICAM-1 and VCAM-1, CTL adheres to the vascular endothelium and migrates to tumors. known to reduce performance. Furthermore, blocking the release of chemokines such as CXCL9, 10, and 11, which are ligands of CXCR3, from intratumoral dendritic cells prevents CTL from adhering to vascular endothelium and inhibits intratumoral invasion.