title: High leukocyte mtDNA content contributes to poor prognosis through ROS-mediated immunosuppression in hepatocellular carcinoma patients.
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.
authors.affiliation: Department of General Surgery, Tangdu Hospital, The Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Xianli
authors.initials: X
authors.lastname: He
authors.affiliation: Department of General Surgery, Tangdu Hospital, The Fourth Military Medical University, Xi'an 710032, China.|State Key Laboratory of Cancer Biology and Experimental Teaching Center of Basic Medicine, The Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Falin
authors.initials: F
authors.lastname: Qu
authors.affiliation: Department of General Surgery, Tangdu Hospital, The Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Zhou
authors.affiliation: State Key Laboratory of Cancer Biology and Experimental Teaching Center of Basic Medicine, The Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Xingchun
authors.initials: X
authors.lastname: Zhou
authors.affiliation: State Key Laboratory of Cancer Biology and Experimental Teaching Center of Basic Medicine, The Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Yibing
authors.initials: Y
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Cancer Biology and Experimental Teaching Center of Basic Medicine, The Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Xu
authors.initials: X
authors.lastname: Guo
authors.affiliation: State Key Laboratory of Cancer Biology and Experimental Teaching Center of Basic Medicine, The Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Jibin
authors.initials: J
authors.lastname: Li
authors.affiliation: State Key Laboratory of Cancer Biology and Experimental Teaching Center of Basic Medicine, The Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Qichao
authors.initials: Q
authors.lastname: Huang
authors.affiliation: Department of Radioactive Intervention, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai 200438, China.
authors.forename: Yefa
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Pain Treatment, Tangdu Hospital, The Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Zhuomin
authors.initials: Z
authors.lastname: Lyu
authors.affiliation: Department of Pain Treatment, Tangdu Hospital, The Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Hongxin
authors.initials: H
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Cancer Biology and Experimental Teaching Center of Basic Medicine, The Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Jinliang
authors.initials: J
authors.lastname: Xing
mesh_terms: D000328:Adult; D000368:Aged; D006528:Carcinoma, Hepatocellular / Q000276:immunology / Q000401:mortality / Q000473:pathology*; D004272:DNA, Mitochondrial / Q000276:immunology / Q000378:metabolism*; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007108:Immune Tolerance / Q000502:physiology*; D053208:Kaplan-Meier Estimate; D007963:Leukocytes, Mononuclear / Q000378:metabolism*; D008113:Liver Neoplasms / Q000276:immunology / Q000401:mortality / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D017382:Reactive Oxygen Species / Q000276:immunology / Q000378:metabolism
chemical_list: D004272:DNA, Mitochondrial; D017382:Reactive Oxygen Species
keywords: hepatocellular carcinoma; immunosuppression; mitochondrial DNA content; prognosis; reactive oxygen species