Citrullinated histone H3 as a novel prognostic blood marker in patients with advanced cancer

Abstract

Citrullinated histone H3 (H3Cit) is a central player in the neutrophil release of nuclear chromatin, known as neutrophil extracellular traps (NETs). NETs have been shown to elicit harmful effects on the host, and were recently proposed to promote tumor progression and spread. Here we report significant elevations of plasma H3Cit in patients with advanced cancer compared with age-matched healthy individuals. These elevations were specific to cancer patients as no increase was observed in severely ill and hospitalized patients with a higher non-malignant comorbidity. The analysis of neutrophils from cancer patients showed a higher proportion of neutrophils positive for intracellular H3Cit compared to severely ill patients. Moreover, the presence of plasma H3Cit in cancer patients strongly correlated with neutrophil activation markers neutrophil elastase (NE) and myeloperoxidase (MPO), and the inflammatory cytokines interleukin-6 and -8, known to induce NETosis. In addition, we show that high levels of circulating H3Cit strongly predicted poor clinical outcome in our cohort of cancer patients with a 2-fold increased risk for short-term mortality. Our results also corroborate the association of NE, interleukin-6 and -8 with poor clinical outcome. Taken together, our results are the first to unveil H3Cit as a potential diagnostic and prognostic blood marker associated with an exacerbated inflammatory response in patients with advanced cancer.

Citrullinated histone H3, a biomarker for neutrophil extracellular trap formation, predicts the risk of mortality in patients with cancer

“…With regard to the prognostic impact of H3Cit and cfDNA on the risk of all‐cause mortality, our data are in line with previous findings reporting an association of biomarkers of NET formation with disease severity and reduced survival in patients with cancer (Mangold et al , ; Yang et al , ; Richardson et al , ; Thålin et al , ). Biomarkers of NET formation have been linked to tumour progression and metastatic spread, and could thereby explain poor prognosis of patients (Cools‐Lartigue et al , ; Arelaki et al , ).…”

“…These observations are supported by our study in which the association between H3Cit and mortality was high in cancer types with poor prognosis, namely lung cancer and pancreatic cancer, although we cannot exclude a multiple comparisons problem in subgroup analyses (https://seer.cancer.gov/archive/csr/1975_2014/browse_csr.php?sectionSEL=1%26pageSEL=sect_01_table.05.htmlml). Furthermore, these results are substantiated by a recent study that reported higher H3Cit levels in patients with advanced cancer (Thålin et al , ).…”

Neutrophil Extracellular Traps in the Second Decade

“…Interestingly, administration of DNase 1 or an inhibitor of NE reduced the metastatic burden to control levels. Although NETs have not been presented directly, in a cohort of patients with advanced cancer elevated levels of citrullinated histone 3 (H3Cit) were found, which was not the case in age-matched individuals [73]. H3Cit could serve as a prognostic marker since in the analyzed cohort high levels of serum H3Cit strongly correlated with a poor clinical outcome.…”

The interplay between neutrophils and microbiota in cancer

“…NETs then bind pathogens and bombard them with antimicrobial granule peptides to kill them or opsonize them for phagocytosis . Cancer patients show high levels of NET biomarkers, such as citrullinated histone H3, in their blood . The tumor microenvironment matrix may also dictate NET formation.…”

“…The hypoxic environment of a tumor or the gut may also contribute to NETosis as it increases neutrophil adhesion, degranulation, and toxicity . NETs may accelerate tumorigenesis as ROS, RNS, neutrophil elastase (NE), cathepsin G, and matrix metalloproteinases (MMPs) released by NETs may promote DNA mutations, mitogenesis, inhibit T‐cell activation, and spur on tumor invasion and metastasis . Toxic NETs damage endothelial and epithelial cells, and contribute to kidney dysfunction and thrombosis, namely in autoimmune patients.…”