Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2023 Mar 13:14:1135086.
doi: 10.3389/fimmu.2023.1135086. eCollection 2023.

Neutrophil extracellular traps in tumor progression and immunotherapy

Meina Yan  1 , Yifeng Gu  2 , Hongxia Sun  3 , Qinghong Ge  1
Affiliations
Review

Neutrophil extracellular traps in tumor progression and immunotherapy

Meina Yan et al. Front Immunol. .

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.

Keywords: anti-tumor immunity; immunotherapy; neutrophil extracellular traps; tumor microenvironment; tumor progression.

PubMed Disclaimer

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Schematic representation of NET formation. Different stimuli, such as PMA, tumor-associated stimuli, immunological stimuli, IL-1β, IL-17, IL-18, IL-33, LPS, PAMPs, some antibodies, activated platelets, bacteria, viruses, Ca2+ can induce NET formation. For lytic NETosis, external stimuli produce different kinds of ROS-inducing receptors, activating neutrophils to produce intracellular ROS, ROS further activates MPO and PAD4, then MPO activates NE and PAD4 citrullinates H3, therefore, leads to nuclear envelope disintegration, chromatin decondensation, cell membrane breakdown, NET formation. For non-lytic NETosis, some stimuli, such as Staphylococcus aureus and Candida albicans-associated LPS and HMGB1 can induce NET formation through a non-lytic manner.
Figure 2
Figure 2
NETs promote tumor progression via many molecular pathways. NET can increase tumor cell proliferation by activating TLR9-NFκB-STAT3-p38 pathway; NET-DNA increased MMP-2 and -9 production, which increased tumor growth; NE released by NETs, can enhance tumor growth by activating TLR4-p38-PGC-1α pathway; HMGB1, released by NETs, can promote tumor growth by RAGE-IL-8 axis. Moreover, NETs promote tumor metastasis by promoting EMT, activating TLR4/9-COX2, IL-1β-EGFR-ERK, CCDC25-ILK-β-parvin, and lncRNA MIR503HG-NLRP3 pathway. Besides, NETs-associated NE, MMP-9, and HMGB1 contribute to tumor therapy resistance.
Figure 3
Figure 3
Schematic representation of NET in regulating immune cells. NETs can mediate immune response via complex regulations at multiple immune cells. Macrophages and DCs: NETs promote macrophages apoptosis, polarization, cytokine production, and impair macrophage phagocytic function; NETs can promote DCs apoptosis, maturation, activation and cytokine production. NK cells: NETs can impair NK cell function, including IFN-γ production and cell degranulation. T cells: NETs promote CD4+ T cell differentiation into Th1 and Th17 cell; NETs also promote immature DCs differentiation into CD4+FOXP3+Tregs.B cells: NETs can induce B cells proliferation, activation, differentiation and antibody secretion.
Figure 4
Figure 4
The emerging roles of NETs in the modulation of anti-tumor immunity and immunotherapy. NETs can promote CD4+ and CD8+ T cells exhaustion and dysfunction; NET-mediated physical barrier decreases the contact of immune cytotoxic cells (CD8+ T cell, NK cell and CAR-T cell) with tumor cells; NETs promote the differentiation of naïve CD4+ T cells into Tregs, which further contribute to tumor initiation and progression; NETs promote macrophage M0, NK cell resting. Degradation of NETs by DNase I can enhance the efficiency of tumor immunotherapy; NET/DC vaccine may be used for leukemia treatment.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Poggio M, Hu T, Pai CC, Chu B, Belair CD, Chang A, et al. . Suppression of exosomal PD-L1 induces systemic anti-tumor immunity and memory. Cell (2019) 177(2):414–27.e13. doi: 10.1016/j.cell.2019.02.016 - DOI - PMC - PubMed
    1. Banta KL, Xu X, Chitre AS, Au-Yeung A, Takahashi C, O'Gorman WE, et al. . Mechanistic convergence of the TIGIT and PD-1 inhibitory pathways necessitates co-blockade to optimize anti-tumor CD8(+) T cell responses. Immunity (2022) 55(3):512–26.e9. doi: 10.1016/j.immuni.2022.02.005 - DOI - PMC - PubMed
    1. Tian S, Chu Y, Hu J, Ding X, Liu Z, Fu D, et al. . Tumour-associated neutrophils secrete AGR2 to promote colorectal cancer metastasis via its receptor CD98hc-xCT. Gut (2022) 71(12):2489–501. doi: 10.1136/gutjnl-2021-325137 - DOI - PubMed
    1. Rayes RF, Mouhanna JG, Nicolau I, Bourdeau F, Giannias B, Rousseau S, et al. . Primary tumors induce neutrophil extracellular traps with targetable metastasis promoting effects. JCI Insight (2019) 5(16). doi: 10.1172/jci.insight.128008 - DOI - PMC - PubMed
    1. Brinkmann V, Reichard U, Goosmann C, Fauler B, Uhlemann Y, Weiss DS, et al. . Neutrophil extracellular traps kill bacteria. Science (2004) 303(5663):1532–5. doi: 10.1126/science.1092385 - DOI - PubMed

Publication types

Grants and funding

This work was supported by Suzhou Science and Technology Development Plan Project (SYS2020166), Jiangsu Provincial Commission of Health and Family Planning (H2019064) and Suzhou Gusu Health talent Research Project (GSWS2021038).

LinkOut - more resources