IDO is a heme-containing enzyme in cells and is the rate-limiting enzyme for the metabolism of tryptophan to kynurenine. IDO is mainly expressed in antigen-presenting cells such as dendritic cells, monocytes and macrophages. Many studies have shown that IDO can be up-regulated in tumor tissues, and the expression of IDO may be associated with poor prognosis in cancer patients [15–18]. However, the number of cases included in many studies is limited, and results from these studies are still not comprehensive. This current meta-analysis comprehensively assessed the relationship between IDO expression and prognosis of solid tumor patients.
In this study, we systematically assessed IDO expression level and prognostic indicators of 3939 solid tumor patients from 29 different studies. Our results showed that high expression of IDO predicted poor OS and TTP in cancer patients. However, the results from this meta-analysis indicated that there was significant heterogeneity between these studies. We conducted subgroup analysis by study location, detection method, sample size and study type. Subgroup analysis suggested that the associations between IDO expression and poor OS and poor TTP were significant according to different study locations, detection methods and sample size. However, the heterogeneity could not be reduced through these several subgroup analysis methods. Significantly reduced heterogeneity in the prospective studies suggested that the type and quality of included literature may have affected the level of heterogeneity on OS. Since there was no enough information, our meta-analysis excluded some studies, and most of these studies were consistent with our results[45–47]. Only one study showed that high IDO mRNA expression was associated with favorable prognostic value in basal-like breast carcinoma, but this study only provided metastasis-free survival data in basal-like breast carcinoma[48]. Therefore, excluding these studies did not affect the conclusion of our meta-analysis. In addition, some reviews supported our findings that high expression of IDO was associated with poor prognosis in patients with solid tumors[49, 50].
The mechanisms by which high IDO expression contributes to tumor progression may be based on the following reasons. Highly expressed IDO in tumor tissues can cause immunosuppressive microenvironment, leading to uncontrolled tumor progression. IDO is a rate-limiting enzyme in which tryptophan is metabolized into kynurenine. The high expression and activity of IDO leads to a large consumption of tryptophan in the cell microenvironment, which makes the cells in a "tryptophan starvation" state. Depletion of tryptophan causes T cells arrest in the G1 phase of cell cycle, thereby inhibiting T cell proliferation. The main metabolite of tryptophan degradation, kynurenine, also has a direct toxic effect on T cells and induces T cell apoptosis. Kynurenine is also a natural ligand for aryl hydrocarbon receptors. By activating aryl hydrocarbon receptors, kynurenine can regulate the differentiation direction of Th17/Treg cells, thereby promoting the balanced differentiation of Th17/Treg to Treg cells [3, 7, 9]. In addition, the IDO inhibitors improve responses to cancer chemotherapy, suggesting that the IDO highly expressed cells may have chemoresistance in cancer [51].
Our study further enhanced the view that high expression of IDO has a poor prognosis for cancer patients by performing meta-analysis on a large number of research data. In addition, this meta-analysis also gives hints on several other aspects. First, the high expression of IDO may be a universal prognostic biomarker for solid tumors. We analyzed 10 different types of solid tumors, including colorectal cancer, endometrial cancer, renal cell carcinoma, hepatocellular carcinoma, etc. Secondly, we verified that both Asian patients and other country patients harboring high expression of IDO were highly correlated with poor prognosis in patients with solid tumors, which did not vary because of ethnic differences. Moreover, our results suggested that the IDO expression can be used as a more widely used prognostic marker. Finally, this study suggested that IDO had the potential to develop into a prognostic marker and a therapeutic target for solid tumors.
It should be noted that, there were limitations in this meta-analysis. First, the definitions of IDO positive and high expression were not completely consistent between studies, which may cause heterogeneity between studies. Secondly, due to limitations from the other included studies and large number of tumor types, we were unable to perform a subgroup analysis for each type of tumor. Thirdly, we extracted the HRs data directly from the original literature, and these data were reliable than calculated HRs indirectly deducted from the literature. However, some studies did not provide complete data and were excluded from statistics, hence some missing information might have reduced the power of IDO as a prognostic marker in solid tumor patients.