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.

Elevated Mitochondrial DNA Copy Number in Peripheral Blood and Tissue Predict the Opposite Outcome of Cancer: A Meta-Analysis

“…Previous studies have demonstrated the interaction between various immune cells giving rise to the change of the immunological environment contributes to the underlying association. It has been reported that patients with high leukocyte mtDNA copy number have had increased Tregs and decreased NK-cells in peripheral blood, and Tregs were considered as inhibiting anticancer immunity while NK cells served as immunosurveillant, suggesting the patients with high mtDNA copy number awere in the immunosuppressive state2155. Moreover, the previous study also showed patients with high plasma mtDNA copy number held lower plasma TNF-α and IFN-ɣ but higher TGF-β1 concentrations21.…”

“…After a thorough review of titles and abstracts by two investigators independently, 394 studies were excluded and the full texts of remaining 26 references have also been artificial retrieved for further identification. Finally a total of 20 retrospective studies comprising 5413 patients were included in our study and 18 studies were used for analysis16171819202122252627282930313233343536. Among the included studies for analysis, there were 16 studies recruited Asian patients while 2 studies recruited Caucasian patients.…”

“…It has been reported that patients with high leukocyte mtDNA copy number have had increased Tregs and decreased NK-cells in peripheral blood, and Tregs were considered as inhibiting anticancer immunity while NK cells served as immunosurveillant, suggesting the patients with high mtDNA copy number awere in the immunosuppressive state2155. Moreover, the previous study also showed patients with high plasma mtDNA copy number held lower plasma TNF-α and IFN-ɣ but higher TGF-β1 concentrations21. TNF-α enhanced the functions of NK cell but suppressed the Tregs, whereas the TGF-β1 promoted the proliferation and differentiation of Tregs and inhibited the expansion and functions of helper T cells and killer cells.…”

Altered mitochondrial DNA copy number contributes to human cancer risk: evidence from an updated meta-analysis

“…For example, lower peripheral blood leukocyte mtDNA copy number was correlated with aggressiveness and fast progression of prostate cancer 14 . Also, high mtDNA copy number in peripheral blood may predict a poor prognosis for hepatocellular carcinoma 15 , glioma 16 , colorectal cancer 17 , and head and neck cancer 18 . Taken together, these results suggested that the alteration of mtDNA content might play complicated roles in tumorigenesis and progression in a cancer-specific manner.…”

A functional polymorphism ofSSBP1gene predicts prognosis and response to chemotherapy in resected gastric cancer patients

“…The underlying mechanisms has been partially investigated. Several previous studies have demonstrated that SSBP1 decrease or deletion may lead to chromosome instability [ 11 ], and eventually prompt tumorigenesis [ 27 ], conversely, overexpression of SSBP1 also may contribute to tumor initiation through increasing mtDNA replication, thus leading to greater energy supplying and enhanced immunosuppression to facilitate tumor growth [ 28 ]. Collectively, these researches highlighted the vital role of SSBP1 in tumor initiation and progression, making SSBP1 an attractive tumor biomarker.…”