Neutrophil Extracellular Traps (NETs): Opportunities for Targeted Therapy
D V Volkov1, G V Tetz2, Y P Rubtsov1
1Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry RAS, Moscow, 117997 Russia.
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.
Insights
Advanced cancers resist therapy, especially solid tumors, due to the tumor microenvironment (TME). Neutrophil extracellular traps (NETs) in the TME impede CAR-T cell therapy. DNase I may overcome this resistance by degrading NETs.
Area of Science:
- Immunology
- Oncology
- Biochemistry
Background:
- Adoptive immunotherapy, particularly CAR-T cells, shows promise against hematological malignancies but faces challenges with solid tumors.
- The tumor microenvironment (TME) is a key factor in solid tumor resistance to antitumor therapies.
- Neutrophils and their extracellular traps (NETs) are increasingly recognized as significant contributors to the immunosuppressive TME and tumor progression.
Purpose of the Study:
- To investigate the role of neutrophil extracellular traps (NETs) in mediating resistance of solid tumors to CAR-T cell therapy.
- To explore the potential of deoxyribonuclease I (DNase I) as a therapeutic agent to degrade NETs and enhance CAR-T cell efficacy within the TME.
- To review current strategies for mitigating the suppressive effects of NETs in the tumor microenvironment.
Main Methods:
- Literature review of studies on CAR-T cell therapy, tumor microenvironment, neutrophils, NETs, and DNase I.
- Analysis of the mechanisms by which NETs contribute to immune evasion and therapeutic resistance in solid tumors.
- Evaluation of preclinical data and proposed therapeutic strategies involving DNase I for NET degradation.
Main Results:
- NETs, composed of neutrophil DNA, form a physical barrier hindering CAR-T cell interaction with tumor cells.
- The presence of NETs within the TME correlates with tumor development and metastasis.
- DNase I has demonstrated potential in degrading NETs, suggesting a strategy to disrupt this barrier.
Conclusions:
- NETs represent a significant obstacle for CAR-T cell-based antitumor therapy in solid tumors.
- Targeting NETs with agents like DNase I holds promise for improving the effectiveness of adoptive immunotherapies.
- Further research into NET-modulating strategies is crucial for advancing cancer treatment.
