Neutrophil Extracellular Traps in Cancer Therapy Resistance

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.

Neutrophil extracellular traps (NETs) reduce the diffusion of doxorubicin which may attenuate its ability to induce apoptosis of ovarian cancer cells

“…Given that NETs can also bind systemically administered DOX in circulating blood, NETs in serum may significantly impair the pharmacokinetics of systemically administrated drugs. Indeed, recent studies have suggested the possibility that NETs may have a role in resistance to chemo-, immuno- or radiotherapy [ 33 ].…”

Neutrophil Transcriptional Deregulation by the Periodontal Pathogen Fusobacterium nucleatum in Gastric Cancer: A Bioinformatic Study

“…PH4B is also linked to chemoresistance [ 29 – 31 ]. Emerging evidence indicates that neutrophil NETosis is a central contributor to cancer proliferation and chemoresistance [ 32 ]. Overall, the identified candidate genes may serve as molecular mechanisms underlying F. nucleatum neutrophil-stimulated NETosis with gastric cancer.…”

Neutrophil extracellular traps: New players in cancer research

“…The molecular mechanisms underlying immune checkpoint blockade resistance are poorly understood and have been the subjects of intense scrutiny in recent years. In several recent studies, NETs have been examined as novel mediators in some tumors that resist checkpoint inhibition (14)(15)(16)(17)(18). Using a PDAC model, Zhang et al demonstrated that IL17 triggered the formation of NETs within tumors, which can lead to the exhaustion of cytotoxic CD8+ T cells in tumors.…”

“…In addition to the roles they play in host defense, NETs have been widely implicated in noninfectious diseases, such as autoimmune diseases (2)(3)(4), rheumatic diseases (5,6), thrombosis (7)(8)(9), diabetes (10), and atherosclerosis (11-13). Increasing evidence indicates that NETs play a critical role in the TME, including in tumor progression, metastasis and therapy resistance (14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28). The effects of NET-related components seem to be intertwined and complicated.…”