Neutrophil Extracellular Traps in Cancer Therapy Resistance

SIMPLE SUMMARY: Neutrophils are a type of white blood cell that also play a role in cancer. They have been shown to influence various aspects of the disease, including resistance to therapy. The role of neutrophils in cancer is now known to involve the extrusion of their DNA in a process called NETosis. The resulting protein-covered DNA webs are called neutrophil extracellular traps (NETs), which have been shown to interact with cancer cells. This interaction is now thought to drive resistance to various cancer therapies, including chemotherapy, immunotherapy, and radiation therapy. The evidence now suggests that NETs may be central facilitators of therapy resistance, bringing cancer cells into proximity with various proteins and factors, and driving multiple mechanisms concurrently. This paper will therefore provide an overview of current evidence implicating NETs in cancer therapy resistance and potential clinical applications. ABSTRACT: Neutrophils and their products are increasingly recognized to have a key influence on cancer progression and response to therapy. Their involvement has been shown in nearly every aspect of cancer pathophysiology with growing evidence now supporting their role in resistance to a variety of cancer therapies. Recently, the role of neutrophils in cancer progression and therapy resistance has been further complicated with the discovery of neutrophil extracellular traps (NETs). NETs are web-like structures of chromatin decorated with a variety of microbicidal proteins. They are released by neutrophils in a process called NETosis. NET-dependent mechanisms of cancer pathology are beginning to be appreciated, particularly with respect to tumor response to chemo-, immuno-, and radiation therapy. Several studies support the functional role of NETs in cancer therapy resistance, involving T-cell exhaustion, drug detoxification, angiogenesis, the epithelial-to-mesenchymal transition, and extracellular matrix remodeling mechanisms, among others. Given this, new and promising data suggests NETs provide a microenvironment conducive to limited therapeutic response across a variety of neoplasms. As such, this paper aims to give a comprehensive overview of evidence on NETs in cancer therapy resistance with a focus on clinical applicability.