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

Table 1 Comprehensive review of indoleamine 2,3-dioxygenase involvement in hepatitis B virus infection, hepatitis C virus infection and hepatocellular carcinoma

Year	Investigator	Description
2004	Ishio et al[54]	IDO is an essential enzyme for anticancer immune reactions of tumor-infiltrating cells. Authors also proposed to clarify the phenotype of IDO-producing cells in PBMC or tumor-infiltrating cells.
2007	Larrea et al[49]	Both human and chimpanzees express hepatic IDO that is directly correlated with CTLA-4. IDO induction may suppress the T-cell reactivity to viral antigens in chronic HCV infection. Hepatic IDO expression declined in animals who recovered from HCV infection.
2008	Pan et al[46]	IDO overexpression is significantly linked with metastasis. IDO may be a novel promising prognostic marker and candidate adjuvant therapeutic target for HCC.
2008	Iwamoto et al[67]	HBV infection helps the IDO induction in response to proinflammatory cytokines, specifically IFN-γ.
2009	Chen et al[51]	IDO associates with viral load and is accountable for immune tolerance against HBV. IDO inhibition can be a novel approach to break tolerance in chronic HBV infection.
2012	Li et al[56]	HCC associated fibroblasts stimulate NK cell dysfunction through PGE2 and IDO and therefore create favorable condition for tumor metastasis.
2013	Higashitani et al[48]	Elevated IDO activity is linked with liver inflammation and fibrosis in chronic HCV patients. In response to the inflammatory stimuli, DCs from patients tend to induce T-regs through IDO dependent mechanism.
2013	Lin et al[55]	IDO overexpression may be associated with poor prognosis in HCC patients.
2014	Han et al[57]	CD14+ CTLA4+ DCs suppressed T-cell response through IDO and IL-10. CD14+ DCs expansion induce systemic immunosuppression in HCC.
2014	Ohtaki et al[68]	IDO inhibition through 1-MT may facilitate in treatment of patients with fulminant hepatitis caused by HBV infection.
2015	Mukhopadhyay et al[58]	High IDO activity and consequent induction of immunosuppressive T-regs promote immune tolerance in tumor tissue. CB1R system is up-regulated in chemically induced HCC, resulting in the induction of various tumor-promoting genes, including, IDO.
2015	Lepiller et al[63]	Hepatic IDO performs a dual role during HCV infection by decelerating viral replication and regulating host immune responses.
2015	Barathan et al[64]	IDO is involved in the onset of immune exhaustion that eventually leads to HCC.
2015	Asghar et al[65]	IDO overexpression in the cirrhotic livers of HCV-infected patients may contribute to the development of HCC. IDO may also serve as therapeutic target against HCV.
2016	Shibata et al[62]	Elevation of L-kynurenine may play a critical role in both the early and late phases of liver carcinogenesis. IDO inhibition may act as an emerging approach for the prevention of liver cancer.
2016	Cheng et al[59]	IDO inhibitors can reverse hepatic CAF-DC regulatory function. IDO may be used as novel immunotherapeutic target for tumor immune escape.
2016	Salem et al[66]	IDO is overexpressed in IFN-α non-responder patient as compared with responder or healthy control. IDO induced immunosuppression may play role in non-responsiveness of chronic HCV patients to IFN-α based therapy.
2016	Zhao et al[60]	IDO is up-regulated in the hepatoma cells and serves as a counter regulatory mechanism stimulated by inflammatory response. IDO may be targeted as immunotherapeutic agent.
2016	Yoshio et al[69]	IDO activation in the early phase followed by a successive increase of chemokines and cytokines is involved in successful HBV clearance in patients with acute hepatitis. IDO possibly acts as a noncytopathic anti-HBV effector.
2016	Ye et al[61]	HIF-1α/CCL20/IDO axis in HCC is crucial for promoting tumor metastasis through both the induction of epithelial-to-mesenchymal transition and the establishment of an immunosuppressive tumor microenvironment.

HCC: Hepatocellular carcinoma; IDO: Indoleamine 2,3-dioxygenase; PBMC: Peripheral blood mononuclear cells; CTLA-4: Cytotoxic T-lymphocyte associated protein-4; DCs: Dendritic cells; NK: Natural killer cells; HCV: Hepatitis C virus; HBV: Hepatitis B virus; PGE2: Prostaglandin E2; T-reg: Regulatory T-cells; HIF-1α: Hypoxia-inducible factor-1α; 1-MT: 1-Methyl tryptophan; CB1R: Cannabinoid receptor 1; CAF: Carcinoma-associated fibroblasts.