Hepatocellular carcinoma from an immunologic perspective

Abstract

Hepatocellular carcinoma is the third most common cancer worldwide. It is an inflammation-associated cancer. Multiple investigators have demonstrated that analysis of the tumor microenvironment may be used to predict patient outcome, indicating the importance of local immune responses in this disease. In contrast with other types of cancer, in which surgery, radiation, and systemic cytotoxic chemotherapies dominate the treatment options, in hepatocellular carcinoma locoregional treatments are widely applied. Such treatments induce rapid tumor cell death and antitumor immune responses, which may favor or impair the patients' outcome. Recent immunotherapeutic studies demonstrating promising results include trials evaluating intratumoral injection of an oncolytic virus expressing granulocyte macrophage colony-stimulating factor, glypican-3 targeting treatments, and anti-CTLA4 treatment. Although some of these novel approaches may provide benefit as single agents, there is a clear opportunity in hepatocellular carcinoma to evaluate these in combination with the standard modalities to more effectively harness the immune response.

Figure 1

HCC a typical inflammation associated carcinoma Acute viral infection is followed by chronic infection, development of liver cirrhosis and HCC. Immune based therapies are used to prevent HCC development at various stages and potentially to treat HCC.

Figure 2

Effect of ablative therapies This figure summarizes immunological effects of different ablative treatments (RFA, HiFU, TACE, cryoablation, oncolytic viruses) on CD4⁺ T cells, CD8⁺ T cells, dendritic cells, NK cells, monocytes, PD1/PDL1 expression and generation of antibody responses.

Figure 3

Immune based combination approaches in HCC. Tumor cells are targeted through different mechanisms such as tumor ablation (TACE, RFA), antibody mediated cytotoxicity or oncolytic viruses, which all lead to antigen release and T cell activation and priming. Tumor specific T cells are activated by different mechanisms (vaccines, cytokines, checkpoint blockade) or by blockade of inhibitory cells (Tregs and MDSC) or inhibitory cytokines and ultimately can kill tumor cells.