Neutrophil Extracellular Traps (NETs): Opportunities for Targeted Therapy

Abstract

Antitumor therapy, including adoptive immunotherapy, inevitably faces powerful counteraction from advanced cancer. If hematological malignancies are currently amenable to therapy with CAR-T lymphocytes (T-cells modified by the chimeric antigen receptor), solid tumors, unfortunately, show a significantly higher degree of resistance to this type of therapy. As recent studies show, the leading role in the escape of solid tumors from the cytotoxic activity of immune cells belongs to the tumor microenvironment (TME). TME consists of several types of cells, including neutrophils, the most numerous cells of the immune system. Recent studies show that the development of the tumor and its ability to metastasize directly affect the extracellular traps of neutrophils (neutrophil extracellular traps, NETs) formed as a result of the response to tumor stimuli. In addition, the nuclear DNA of neutrophils the main component of NETs erects a spatial barrier to the interaction of CAR-T with tumor cells. Previous studies have demonstrated the promising potential of deoxyribonuclease I (DNase I) in the destruction of NETs. In this regard, the use of eukaryotic deoxyribonuclease I (DNase I) is promising in the effort to increase the efficiency of CAR-T by reducing the NETs influence in TME. We will examine the role of NETs in TME and the various approaches in the effort to reduce the effect of NETs on a tumor.

A Neutrophil Extracellular Traps Signature Predicts the Clinical Outcomes and Immunotherapy Response in Head and Neck Squamous Cell Carcinoma

“…It has been reported that the responsiveness of tumor to PD-1 plus CTLA-4 dual checkpoint blockade can be improved by inhibiting NETs. Moreover, the efficiency of CAR-T might be increased by reducing the NETs in TME (Teijeira et al, 2020;Volkov et al, 2021). Furthermore, the NETs has been suggested to be a biomarker to prognose the response of anti-PD-1 therapy in melanoma based on the significant effect of NETs in immunotherapy (Jensen et al, 2021).…”

“…Furthermore, NETs enhance the immune escape of cancer cells. It has been suggested that the NETs might to reduce the curative effect of immune checkpoint inhibitors (ICIs) and chimeric antigen receptor T-cell (CAR-T) immunotherapy (Teijeira et al, 2020;Volkov et al, 2021). In summary, NETs have become a new field of investigation in oncology.…”

The role of neutrophil extracellular traps in cancer progression, metastasis and therapy

“…NETs have recently been linked to cancer resistance and immunotherapy. Previous studies have shown that deoxyribonuclease I (DNase I) disruption of NETs is promising in efforts to improve CAR-T efficiency [ 109 ]. In a CRC mouse model, light-regulated release of DNase I sensitized immune checkpoint inhibitors (ICIs) treatment [ 110 ].…”

Intratumoral neutrophil extracellular traps are associated with unfavorable clinical outcomes and immunogenic context in pancreatic ductal adenocarcinoma

“…Immune cell-related extracellular traps (ETs) also influence disease progression and have been used as indicators of prognosis and therapeutic targets in various diseases ( 9 ). ET formation is a form of cell death and is characterized by the production of extracellular webs, consisting of nuclear DNA and granular and cytoplasmic proteins by immune cells after infection, surgery, radiation, or chemotherapy ( 10 ).…”

“…Neutrophils and macrophages are known to produce ETs ( 11 , 12 ). Neutrophil ETs are involved in many tumor processes ( 9 ), they promote tumor cell growth in hepatocellular carcinoma ( 13 ), and promote metastasis ( 14 ). Neutrophil ETs are also involved in mediating the suppression of anti-tumor immune cells.…”