A proposed role for neutrophil extracellular traps in cancer immunoediting

Abstract

Upon activation, neutrophils release fibers composed of chromatin and neutrophil proteins termed neutrophil extracellular traps (NETs). NETs trap and kill microbes, activate dendritic cells and T cells, and are implicated in autoimmune and vascular diseases. Given the growing interest in the role of neutrophils in cancer immunoediting and the diverse function of NETs, we searched for NETs release by tumor-associated neutrophils (TANs). Using pediatric Ewing sarcoma (ES) as a model, we retrospectively examined histopathological material from diagnostic biopsies of eight patients (mean ± SD age of 11.5 ± 4.7 years). TANs were found in six patients and in two of those we identified NETs. These two patients presented with metastatic disease and despite entering complete remission after intensive chemotherapy had an early relapse. NETs were not identified in the diagnostic biopsies of two patients with localized disease and two with metastatic disease. This study is the first to show that TANs in ES are activated to make NETs, pointing to a possible role of NETs in cancer.

Angiotensin converting enzyme inhibitors and angiotensin II receptor antagonist attenuate tumor growth via polarization of neutrophils toward an antitumor phenotype

“…Recently, an interesting role of NETs in tumor immunology has been proposed. 35 The existence of NETs-releasing neutrophils was found in Ewing Sarcoma and authors suggested the hypothesis regarding the role of NETs in tumor. Since NETs contains several components which are highly cytotoxic to tumor cells, 36,37 we believe that increased NETs formation from hypersegmented neutrophils could be another possible mechanism for antitumor activity of neutrophils.…”

“…1,12 The proposed mechanisms regarding antitumor activity of neutrophils are oxidative damage caused by ROS generation, antibody-dependent tumor cell lysis, and NETs formation. 1,12,35 The tumor destruction caused by ROS generation is unlikely, because hypersegmented neutrophils showed decreased ROS generation in response to PMA stimulation (Fig. 4B).…”

The Multifaceted Roles Neutrophils Play in the Tumor Microenvironment

“…By virtue of their ability to present antigens, neutrophils may directly activate a T cell response. Neutrophils may also activate dendritic cells and T cells through release of neutrophil extracellular traps (NETs) [349,350]. On top of secreting T cell chemoattractants, neutrophil-secreted TNFα, Cathepsin G and neutrophil elastase, are able to increase T cell proliferation and cytokine production, which together enhance adaptive immune responses [350].…”

Priming of neutrophils toward NETosis promotes tumor growth

“…NETs have been observed in both murine and human tumors: sarcomas, pancreatic adenocarcinoma and LLC lung carcinomas [11][12][13][14] and have been shown to promote metastasis following septicemia in mice. 15 To evaluate if the presence of PAD4/ NETs in the host affects primary tumor growth, we compared tumor progression in WT mice to PAD4-deficient mice whose neutrophils are defective in NET formation.…”