The expression and function of immunoglobulin-like transcript 4 in dendritic cells from patients with hepatocellular carcinoma

Abstract

Due to their easy availability and expansion in vitro, monocyte-derived dendritic cells (moDCs) are most frequently used for tumor vaccination. Immunoglobulin-like transcript 4 (ILT4), as inhibitory receptor, has been reported to be related to DC tolerance. However, the influence of ILT4 for DC tolerance in hepatocellular carcinoma (HCC) patients has not been illustrated. In this research, we explored the expression of ILT4 on moDCs from HCC patients and its effect on moDC function. We demonstrated that the expression of ILT4 on mature DCs (mDCs) was higher in the peripheral blood from HCC patients than in that from healthy donors. The levels of cytokines IL-1β and IL-6 secreted by mDCs from both HCC patients and healthy controls, stimulated by anti-ILT4 agonistic mAb, were decreased. In contrast, the levels of IL-10 and IL-23 were upregulated. In addition, ILT4, triggered by anti-ILT4 agonistic mAb, could reduce allogeneic T cell proliferation stimulated by the mDCs. Moreover, ILT4 triggered by anti-ILT4 agonistic mAb could also reduce the ability of the mDCs to stimulate tumor cell antigen-specific autologous CD4⁺ T cells (production of IFN-γ) and CD8⁺ T cells (production of IFN-γ and IL-2). Furthermore, ILT4 expression impaired the cytotoxicity of autologous T cells induced by the mDCs against the HCC tumor cell line SMMC-7721. Our data revealed that the high expression of ILT4 promoted the immune tolerance of DCs, resulting in an inefficiency of the T cell response, a process that is exacerbated in HCC patients.

Keywords: Dendritic cells; Hepatocellular carcinoma; ILT4; Immune tolerance.