Mitochondrial DNA in the tumour microenvironment activates neutrophils and is associated with worse outcomes in patients with advanced epithelial ovarian cancer.

Autor: Singel KL; Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA., Grzankowski KS; Department of Surgery, Division of Gynecologic Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.; Arizona Center for Cancer Care, Phoenix, AZ, USA., Khan ANMNH; Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA., Grimm MJ; Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA., D'Auria AC; Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA., Morrell K; Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA., Eng KH; Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA., Hylander B; Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA., Mayor PC; Department of Surgery, Division of Gynecologic Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA., Emmons TR; Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA., Lénárt N; Momentum Laboratory of Neuroimmunology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary., Fekete R; Momentum Laboratory of Neuroimmunology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary., Környei Z; Momentum Laboratory of Neuroimmunology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary., Muthukrishnan U; Department of Pharmacology and Clinical Neuroscience, Umeå University, Umeå, Sweden., Gilthorpe JD; Department of Pharmacology and Clinical Neuroscience, Umeå University, Umeå, Sweden., Urban CF; Department of Clinical Microbiology, Umeå University, Umeå, Sweden., Itagaki K; Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA., Hauser CJ; Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA., Leifer C; Department of Microbiology and Immunology, Cornell University College of Veterinary Medicine, Ithaca, NY, USA., Moysich KB; Department of Cancer Prevention and Control, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA., Odunsi K; Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.; Department of Surgery, Division of Gynecologic Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.; Center for Immunotherapy, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA., Dénes Á; Momentum Laboratory of Neuroimmunology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary., Segal BH; Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA. brahm.segal@roswellpark.org.; Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA. brahm.segal@roswellpark.org.; Department of Medicine, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, USA. brahm.segal@roswellpark.org.
Jazyk: angličtina
Zdroj: British journal of cancer [Br J Cancer] 2019 Jan; Vol. 120 (2), pp. 207-217. Date of Electronic Publication: 2018 Dec 06.
DOI: 10.1038/s41416-018-0339-8
Abstrakt: Background: Advanced cancer causes necrosis and releases damage-associated molecular patterns (DAMPs). Mitochondrial DAMPs activate neutrophils, including generation of neutrophil extracellular traps (NETs), which are injurious, thrombogenic, and implicated in metastasis. We hypothesised that extracellular mitochondrial DNA (mtDNA) in ascites from patients with epithelial ovarian cancer (EOC) would correlate with worse outcomes.
Methods: Banked ascites supernatants from patients with newly diagnosed advanced EOC were analysed for mtDNA, neutrophil elastase, and activation of healthy donor neutrophils and platelets. TCGA was mined for expression of SELP and ELANE.
Results: The highest quartile of ascites mtDNA correlated with reduced progression-free survival (PFS) and a higher likelihood of disease progression within 12-months following primary surgery (n = 68, log-rank, p = 0.0178). NETs were detected in resected tumours. Ascites supernatants chemoattracted neutrophils, induced NETs, and activated platelets. Ascites exposure rendered neutrophils suppressive, based on abrogation of ex vivo stimulated T cell proliferation. Increased SELP mRNA expression correlated with worse overall survival (n = 302, Cox model, p = 0.02).
Conclusion: In this single-centre retrospective analysis, ascites mtDNA correlated with worse PFS in advanced EOC. Mitochondrial and other DAMPs in ascites may activate neutrophil and platelet responses that facilitate metastasis and obstruct anti-tumour immunity. These pathways are potential prognostic markers and therapeutic targets.
Databáze: MEDLINE
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