Dendritic Cell and T Cell Crosstalk in Liver Fibrogenesis and Hepatocarcinogenesis: Implications for Prevention and Therapy of Liver Cancer

Abstract

Liver fibrosis is a chronic, highly prevalent disease that may progress to cirrhosis and substantially increases the risk for development of hepatocellular carcinoma (HCC). Fibrotic livers are characterized by an inflammatory microenvironment that is composed of various immunologically active cells, including liver-resident populations (e.g., Kupffer cells, hepatic stellate cells and sinusoidal endothelium) and infiltrating leukocytes (e.g., monocytes, monocyte-derived macrophages, neutrophils and lymphocytes). While inflammatory injury drives both fibrogenesis and carcinogenesis, the tolerogenic microenvironment of the liver conveys immunosuppressive effects that encourage tumor growth. An insufficient crosstalk between dendritic cells (DCs), the professional antigen presenting cells, and T cells, the efficient anti-tumor effector cells, is one of the main mechanisms of HCC tumor tolerance. The meticulous analysis of patient samples and mouse models of fibrosis-HCC provided in-depth insights into molecular mechanisms of immune interactions in liver cancer. The therapeutic modulation of this multifaceted immunological response, e.g., by inhibiting immune checkpoint molecules, in situ vaccination, oncolytic viruses or combinations thereof, is a rapidly evolving field that holds the potential to improve the outcome of patients with HCC. This review aims to highlight the current understanding of DC-T cell interactions in fibrogenesis and hepatocarcinogenesis and to illustrate the potentials and pitfalls of therapeutic clinical translation.

Keywords: HCC; T cells; antigen-presenting cells; checkpoint inhibitors; cirrhosis; dendritic cell vaccine; dendritic cells; fibrosis; immunotherapy; tumor tolerance.

Figure 1

Dendritic cell (DC)–T cell-tumor interactions as targets of hepatocellular carcinoma (HCC) immunotherapy. HCC tumors employ various strategies of immune evasion. One of them is induction of immature or dysfunctional DCs whose antigen presenting capacity results in a tolerogenic direction of the immune response. (1a) Downregulation of tumor antigens results in (1b) antigen presentation by immature DCs with an instable DC–T cell interaction, leading to a failure to cross-prime CD8 cells and subsequent T cell anergy and tumor tolerance. Similarly, (1c) tumors can directly induce DC immaturity by secreting mediators like IL-10, VEGF and TGF-β. (1d) DCs can actively induce a tolerogenic response by expressing ligands of checkpoint pathways like CTLA-4 or TIM3 while downregulating stimulatory signals, inducing T cell anergy or Tregs, which in turn hamper cytotoxic T cell responses via IL-10. (1e) Tumor cells can evade CD8 control by expressing immune checkpoint ligands like PD-L1 and directly blocking cytotoxic T cells. Checkpoint inhibition of (2a) tumor cells or (2b) antigen-presenting cells leads to the inhibition of the inhibitory signals and results in an unleashed cytotoxic activity. Oncolytic viruses (3a) are injected peripherally and selectively infect HCC cells. Subsequently, a phase of replication with GM-CSF production release follows, GM-CSF recruits APCs to the tumor. (3b) Virus-induced immunogenic cell death results in a release of tumor antigens, which are phagocytized by the recruited DCs, triggering (3c) T cell priming and a systematic cytotoxic antitumor response. For an ex vivo vaccine (4a) mononuclear cells are isolated from the patient‘s blood and incubated with activating signals (granulocyte-colony stimulating factor (G-CSF), IL-4 and TNF-α) and tumor antigens, then transferred back into the patient. (4b) The injected DCs prime CD8+ lymphocytes and trigger an antitumor response. In situ vaccination: (5a) DCs are recruited with, e.g., Ft3l, while (5b) tumor mass is destroyed with radio- or chemotherapy, so that tumor antigens are readily available for (5c) phagocytosis. (5d) Maturation signals such as TLR3 induce antigen presentation to prime CD8+ T cells. A cytotoxic activity ensues. Created with BioRender.com.