The complex role of immune cells in antigen presentation and regulation of T-cell responses in hepatocellular carcinoma: progress, challenges, and future directions

Abstract

Hepatocellular carcinoma (HCC) is a prevalent form of liver cancer that poses significant challenges regarding morbidity and mortality rates. In the context of HCC, immune cells play a vital role, especially concerning the presentation of antigens. This review explores the intricate interactions among immune cells within HCC, focusing on their functions in antigen presentation and the modulation of T-cell responses. We begin by summarizing the strategies that HCC uses to escape immune recognition, emphasizing the delicate equilibrium between immune surveillance and evasion. Next, we investigate the specific functions of various types of immune cells, including dendritic cells, natural killer (NK) cells, and CD8+ T cells, in the process of antigen presentation. We also examine the impact of immune checkpoints, such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and the pathways involving programmed cell death protein 1 (PD-1) and programmed death ligand 1 (PD-L1), on antigen presentation, while taking into account the clinical significance of checkpoint inhibitors. The review further emphasizes the importance of immune-based therapies, including cancer vaccines and CAR-T cell therapy, in improving antigen presentation. In conclusion, we encapsulate the latest advancements in research, propose future avenues for exploration, and stress the importance of innovative technologies and customized treatment strategies. By thoroughly analyzing the interactions of immune cells throughout the antigen presentation process in HCC, this review provides an up-to-date perspective on the field, setting the stage for new therapeutic approaches.

Keywords: CTLA-4; PD-1/PD-L1; dendritic cells; hepatocellular carcinoma; natural killer cells.

Figure 1

Hepatocellular carcinoma (HCC) cancer immunoediting is a dynamic and multifaceted process, comprising the stages of cancer initiation, elimination, equilibrium, and eventual escape. Immune surveillance initially destroys nascent cells, followed by immune equilibrium controlling growth. Over time, HCC evades detection, leading to progression. Understanding these stages reveals the complex immune-HCC relationship, emphasizing therapeutic potential.

Figure 2

Immune cells play a pivotal role in HCC antigen presentation. (A) Antigen presentation by immune cells orchestrates anticancer responses. Dendritic cells (DCs) capture antigens and present to CD8+ T cells, with CD4+ T cells enhancing this process. HCC develops immune escape mechanisms, impairing antigen presentation. In-depth study may reveal new immunotherapy targets. (B) DCs capture and process antigens for presentation to CD8+ T cells. NK cells directly kill HCC cells. CD4+ T cells assist in antitumor immunity. HCC employs immune escape mechanisms; comprehensive understanding is crucial for treatment strategies.

Figure 3

Combination therapies hold great potential for HCC. (A, B) Pancreatic cancer in the context of HCC often requires multifaceted treatment. The combination of immune checkpoint inhibitors with tyrosine kinase inhibitors or locoregional therapies is an attractive strategy, aiming to synergistically impede tumor growth, etc. This leverages complementary mechanisms of different treatments, laying the foundation for effective therapy. (C) Blocking CTLA-4 or PD-1 signaling is a promising approach in HCC immunotherapy. These checkpoints regulate T cell activity and are exploited by tumor cells to evade immune surveillance. Inhibitors targeting them release T cell responses. Clinical trials show encouraging results, potentially revolutionizing HCC treatment. Manipulating these pathways is a promising strategy to enhance immunity and improve outcomes.