Neutrophil extracellular traps in tumor progression and immunotherapy

Abstract

Tumor immunity is a growing field of research that involves immune cells within the tumor microenvironment. Neutrophil extracellular traps (NETs) are neutrophil-derived extracellular web-like chromatin structures that are composed of histones and granule proteins. Initially discovered as the predominant host defense against pathogens, NETs have attracted increasing attention due to they have also been tightly associated with tumor. Excessive NET formation has been linked to increased tumor growth, metastasis, and drug resistance. Moreover, through direct and/or indirect effects on immune cells, an abnormal increase in NETs benefits immune exclusion and inhibits T-cell mediated antitumor immune responses. In this review, we summarize the recent but rapid progress in understanding the pivotal roles of NETs in tumor and anti-tumor immunity, highlighting the most relevant challenges in the field. We believe that NETs may be a promising therapeutic target for tumor immunotherapy.

The impact of NETosis on hematological malignancies as a promising therapeutic target

“…Neutrophils play a significant role in cancer initiation, progression, metastasis, and resistance to treatment in different types of cancers, including lung, ovarian, blood, pancreas, breast, and colon. The TME consists of various cell types, including adaptive cells (T and B cells), innate immune cells (macrophages, neutrophils, dendritic cells (DCs), natural killer (NK) cells, myeloid-derived suppressor cells (MDSCs)), stromal cells (fibroblasts, pericytes, and mesenchymal stromal cells) and extracellular matrix (ECM) cells (12,13). After synthesis and maturation in the bone marrow, neutrophils are released into the blood and recruited to the infection or tumor sites.…”

“…Neutrophils are recruited and infiltrated into the tumors, called TAN, divided into two groups, N1 and N2. NI represents an anti-tumor phenotype associated with high expression of TNF-a, intercellular adhesion molecule 1 (ICAM-1), and chemokine ligand 2 (CCL2) (12)(13)(14). On the other hand, N2 represents a tumor-promoting effect associated with elevated levels of CCL2, CCL3, CCL4, CCL8, CCL12, CCL17, chemokine ligand 1 (CXCL1), CXCL2, CXCL16 and interleukin 8 (IL-8) and induced NETosis (12).…”

“…Neutrophil-induced ROS causes inflammation and endothelial damage involved in cancer progression and metastasis. ROS molecules such as hydrogen peroxide (H 2 O 2 ) act as messengers that regulate cell signaling pathways, including MAPK/Erk1/2, PI3K/Akt, and IKK/NF-K B, which are involved in cancer progression (13,15,18).…”

The crucial regulatory role of type I interferon in inflammatory diseases

“…This abnormal production of IFN-I can promote the differentiation of B cells to plasma blasts, leading to inflammation and tissue damage [ 207 , 208 ]. Additionally, neutrophils may also contribute to the perpetuation of the immune response in SLE through the release of neutrophil extracellular traps (NETs), which could activate pDCs to secrete IFN-Is [ 209 ].…”

Structure–Activity Relationship of PAD4 Inhibitors and Their Role in Tumor Immunotherapy

“…Genetic lockout or chemical inhibition of PAD4 results in the inability of neutrophils to form citrullinate histones and failure in NETosis [ 17 ]. Meanwhile, abnormal increases in NETs promote immune rejection and inhibit T-cell-mediated antitumor immune responses [ 18 ]. Therefore, PAD4 is one of the indispensable members of the mammalian immune system.…”