Low Indoleamine 2,3-Dioxygenase 1 Expression Enhances Dendritic Cells Response to Tumor Cells Against Hepatocellular Carcinoma.

Abstract

Aim: To investigate the effect of IDO1 expression levels in HCC on the distribution, infiltration, and anti-tumor immune response of mature DCs.

Methods: Multiplex immunohistochemical staining was applied to detect the expression level of IDO1 and the infiltration of DCs in the HCC tissue microarray, including total 96 human HCC samples and 82 samples of matched adjacent normal tissues. In vitro, CCK-8, Key Fluor 488 Click-iT Edu, wound healing, and transwell assays were performed to explore the effect of IDO1 on the viability, proliferation, migration and invasion ability of HCC cell line SK-HEP1. In vivo, a subcutaneous xenograft tumor model of nude mice was established by subcutaneously inoculating SK-HEP1 and treated with IDO1 catalytic inhibitor epacadostat (EPA) to observe the effect of IDO1 on tumor growth and immune cells infiltration.

Results: Results of clinical tissue microarrays showed that compared with corresponding paracancerous tissues, the infiltration of mature DCs was significantly reduced in HCC cancer tissues with high expression of IDO1. Meanwhile, IDO1 was highly expressed in HCC cancer tissues with pathological grade I-II, high AFP levels (≥200µg/L), HBV-positivie, cirrhosis, distant metastasis and recurrence. Survival analysis showed that low IDO1 and high mature DCs cell infiltration were significantly associated with superior overall survival (OS). Correlation analysis further showed that IDO1 was negatively correlated with mature DCs. The in vitro cellular and in vivo animal experiments in this study showed that inhibition IDO1 helped to decrease the malignant biological behavior of HCC and enhance the response of immune cells to tumor cells.

Conclusion: IDO1 suppresses anti-tumor immunity in HCC, at least in part, by curtailing mDC infiltration. Targeting IDO1 may represent a promising immunotherapeutic strategy. However, its immunomodulatory effects must be validated in immunocompetent or humanized animal systems before clinical translation.