Indoleamine 2,3-dioxygenase: As a potential prognostic marker and immunotherapeutic target for hepatocellular carcinoma

Abstract

Tumor cells induce an immunosuppressive microenvironment which leads towards tumor immune escape. Understanding the intricacy of immunomodulation by tumor cells is essential for immunotherapy. Indoleamine 2,3-dioxygenase (IDO) is an immunosuppressive enzyme which mediates tumor immune escape in various cancers including hepatocellular carcinoma (HCC). IDO up-regulation in HCC may lead to recruitment of regulatory T-cells into tumor microenvironment and therefore inhibit local immune responses and promote metastasis. HCC associated fibroblasts stimulate natural killer cells dysfunction through prostaglandin E2 and subsequently IDO promotes favorable condition for tumor metastasis. IDO up-regulation induces immunosuppression and may enhance the risk of hepatitis C virus and hepatitis B virus induced HCC. Therefore, IDO inhibitors as adjuvant therapeutic agents may have clinical implications in HCC. This review proposes future prospects of IDO not only as a therapeutic target but also as a prognostic marker for HCC.

Keywords: Hepatitis C virus, Hepatitis B virus; Hepatocellular carcinoma; Indoleamine 2,3-dioxygenase.

Figure 1

Immunosuppressive role of indoleamine 2,3-dioxygenase in human hepatocellular carcinoma. Indoleamine 2, 3-dioxygenase (IDO) expression is constitutively induced in both IDO⁺ tumor cells and plasmacytoid dendritic cells (DCs) by exposure to IFN-γ. The effector function of the antigen-specific T cells is impaired because of tryptophan degradation via IDO at tumor site, which in turn affects the immune-mediated control of tumor growth. A tolerogenic microenvironment is created by regulatory DCs resulting in the increased number of T-regs and reduced number of antigen-specific T cells leading to cell cycle arrest and apoptosis. IDO⁺ tumor cells lead to down-regulation of activating NK cell receptors.