Tumor Immune Microenvironment and Immunosuppressive Therapy in Hepatocellular Carcinoma: A Review

Abstract

Liver cancer has the fourth highest mortality rate of all cancers worldwide, with hepatocellular carcinoma (HCC) being the most prevalent subtype. Despite great advances in systemic therapy, such as molecular-targeted agents, HCC has one of the worst prognoses due to drug resistance and frequent recurrence and metastasis. Recently, new therapeutic strategies such as cancer immunosuppressive therapy have prolonged patients' lives, and the combination of an immune checkpoint inhibitor (ICI) and VEGF inhibitor is now positioned as the first-line therapy for advanced HCC. Since the efficacy of ICIs depends on the tumor immune microenvironment, it is necessary to elucidate the immune environment of HCC to select appropriate ICIs. In this review, we summarize the findings on the immune microenvironment and immunosuppressive approaches focused on monoclonal antibodies against cytotoxic T lymphocyte-associated protein 4 and programmed cell death protein 1 for HCC. We also describe ongoing treatment modalities, including adoptive cell transfer-based therapies and future areas of exploration based on recent literature. The results of pre-clinical studies using immunological classification and animal models will contribute to the development of biomarkers that predict the efficacy of immunosuppressive therapy and aid in the selection of appropriate strategies for HCC treatment.

Keywords: adaptive cell transfer-based therapy; chimeric antigen receptor; chronic hepatitis; cytokine-induced killer; fibrosis; hepatocellular carcinoma; immune checkpoint inhibitor; immunotherapy; molecular target agent; tumor microenvironment.

Figure 1

Seven steps of the cancer-immunity cycle in hepatocellular carcinoma (HCC). (a) Cancer antigens are released from HCC cells that have died due to proliferation necrosis or treatment. (b) Dendritic cells (DCs) that capture cancer antigens or phagocytose dead HCC cells migrate to the lymph node. (c) DCs digest cancer antigens, place them on MHC class I molecules as antigen peptides, and present them to CD8+ cytotoxic T lymphocytes (CTLs) in the lymph node. (d) T cells migrate to HCC tissue. (e) T cells infiltrate to the tumor. (f) T cells recognize HCC cells via T cell receptors (TCR). The co-stimulatory receptors CD28 and CD137 bind to ligands CD80/CD86 and CD137L on DCs, respectively. (g) T cells kill HCC cells. Inflammatory cytokines tumor necrosis factor (TNF)-β and interleukin (IL)-12 induced by M1 macrophages, interferon (IFN)-γ produced by Th1 and natural killer (NK) cells, and IL-2 secreted by CTLs fuel further T cell activation. Checkpoint molecules CTL-associated protein-4 (CTLA-4) and programmed cell death protein-1 (PD-1) bind to CD80/CD86 and PD-ligand 1 (PD-L1)/PD-L2 on DCs, respectively, suppress T cells, and control excessive immune response (right part of Figure 1). The immunity cycle is equipped with a negative feedback mechanism; when excessively suppressed, the cycle is stopped along with the amplification of the cancer immune response. Even if immunosuppressive factors and cells become significant and tumor microenvironment (TME) is established, this cycle is stopped, and the immune response is reduced. Epithelial-mesenchymal transition (EMT) in HCC cells induces differentiation of myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs), and regulatory T cells (Tregs) by mesenchyme stem cells (MSCs) and cancer-associated fibroblasts (CAFs). Immunosuppressive cytokines such as IL-10, transforming growth factor (TGF)-β, indoleamine 2,3-dioxygenase (IDO), and prostaglandin E2 (PGE2) are also involved, and the expression of PD-1 on CTLs and PD-L1/PD-L2 on DCs is increased. T cell activation is further attenuated through direct suppression of Tregs against CTLs and trans-endocytosis of CD80/CD86 on DCs by Tregs (left side of Figure 1).