NETosis as an oncologic therapeutic target: a mini review

Abstract

Neutrophil Extracellular Traps (NETs) are a key form of pro-inflammatory cell death of neutrophils characterized by the extrusion of extracellular webs of DNA containing bactericidal killing enzymes. NETosis is heavily implicated as a key driver of host damage in autoimmune diseases where injurious release of proinflammatory enzymes damage surrounding tissue and releases 70 known autoantigens. Recent evidence shows that both neutrophils and NETosis have a role to play in carcinogenesis, both indirectly through triggering DNA damage through inflammation, and directly contributing to a pro-tumorigenic tumor microenvironment. In this mini-review, we summarize the current knowledge of the various mechanisms of interaction and influence between neutrophils, with particular attention to NETosis, and cancer cells. We will also highlight the potential avenues thus far explored where we can intercept these processes, with the aim of identifying promising prospective targets in cancer treatment to be explored in further studies.

Keywords: NETosis; cancer; innate immunity; neutrophil; tumor microenvironment.

Figure 1

(A) Molecular process of vital and suicidal NETosis. The two forms of NETosis include suicidal NETosis and vital NETosis. Suicidal NETosis involves the dissolution of the plasma membrane while vital NETosis preserves the membrane with exodosis of NETs via vesicles. The two pathways converge upon the activation of PAD4, NE and MPO which leads to histone hypercitrullination, chromatin decondensation, the formation of NETs and the disruption of nuclear membrane. (B) Polarization of N1/N2 neutrophils in the tumour microenvironment (TME) and the effect of NETs on tumour and surrounding cells. Neutrophils in the TME are polarized towards either N1 or N2 phenotypes, which is determined by the influence of factors produced by surmunding NK cells and tumour cells. N2 neutrophils that undergo NETosis release a myriad of molecules and enzymes that have immunosuppressive and pro-tumour properties as well as causing damage to surrounding epithelial cells. In turn tumour cells release various factors that induce the polarization, recruitment, and trigger NETosis in N2 neutrophils.