High leukocyte mtDNA content contributes to poor prognosis through ROS-mediated immunosuppression in hepatocellular carcinoma patients.

Xianli He,Feng Zhou,Yibing Chen,Yefa Yang,Jibin Li,Xu Guo,Falin Qu,Zhuomin Lyu,Hongxin Zhang,Xingchun Zhou,Jinliang Xing,Qichao Huang

doi:10.18632/oncotarget.8071

Xianli He, Feng Zhou + Show 10 more

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https://doi.org/10.18632/oncotarget.8071

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Abstract

Compelling epidemiological evidences indicate a significant association between leukocyte mitochondrial DNA (mtDNA) content and incidence risk of several malignancies, including hepatocellular carcinoma (HCC). However, whether leukocyte mtDNA content affect prognosis of HCC patients and underlying mechanism has never been explored. In our study, leukocyte mtDNA content was measured in 618 HCC patients and its prognostic value was analyzed. Moreover, we detected the immunophenotypes of peripheral blood mononuclear cells (PBMCs) and plasma concentrations of several cytokines in 40 HCC patients and assessed the modulating effects of mtDNA content on immunosuppression in cell models. Our results showed that HCC patients with high leukocyte mtDNA content exhibited a significantly worse recurrence-free survival (RFS) and overall survival (OS) than those with low leukocyte mtDNA content. Leukocyte mtDNA content and TNM stage exhibited a notable joint effect in prognosis prediction. Furthermore, we found that patients with high leukocyte mtDNA content exhibited a higher frequency of CD4+CD25+FOXP3+ regulatory T (Treg) cells and lower frequency of NK cells in PBMCs and had higher TGF-β1 and lower TNF-α and IFN-γ plasma concentration when compared with those with low leukocyte mtDNA content, which suggests an immunosuppressive status. High leukocyte mtDNA content significantly enhanced the ROS-mediated secretion of TGF-β1, which accounted for higher Treg and lower NK frequency in PBMCs. In a conclusion, our study for the first time demonstrates that leukocyte mtDNA content is an independent prognostic marker complementing TNM stage and associated with an ROS-mediated immunosuppressive phenotype in HCC patients.

Highlights

Hepatocellular carcinoma (HCC) is the sixth most common malignant disease and the third leading cause of cancer-related death worldwide [1]
We found that patients with high leukocyte mitochondrial DNA (mtDNA) content exhibited a higher frequency of CD4+CD25+FOXP3+ regulatory T (Treg) cells and lower frequency of natural killer (NK) cells in peripheral blood mononuclear cells (PBMCs) and had higher transforming growth factor (TGF)-β1 and lower tumor necrosis factor (TNF)-α and IFN-γ plasma concentration when compared with those with low leukocyte mtDNA content, which suggests an immunosuppressive status
Xia et al have demonstrated that leukocyte mtDNA content is associated with the T stage of breast cancer, indicating that high mtDNA content may facilitate the progression of cancer [21]

Summary

Introduction

Hepatocellular carcinoma (HCC) is the sixth most common malignant disease and the third leading cause of cancer-related death worldwide [1]. Despite recent improvements in diagnosis and treatment, clinical outcome of HCC is still disappointing [2]. Due to the molecular and genetic heterogeneity, HCC patients with the similar clinical and pathological features often exhibit distinct outcomes [3]. It is urgent to identify new molecular biomarkers to complement TNM staging system for more precise prognostic prediction of HCC, and benefit for individualized therapy. The mtDNA content may undergo significant changes under diverse internal or external microenvironments, which can lead to impairment of the OXPHOS system and the enhanced generation of ROS. This scenario has been proposed to contribute to the initiation and progression of tumors [7]

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