Role of neutrophil extracellular traps in radiation resistance of invasive bladder cancer

Shinde-Jadhav, Surashri; Mansure, José João; Rayes, Roni F.; Marcq, Gautier; Ayoub, Mina; Skowronski, Rodrigo; Kool, Ronald; Brimo, Fadi; Spicer, Jonathan; Kassouf, Wassim

doi:10.1038/s41467-021-23086-z

Cited by 127 publications

(121 citation statements)

References 67 publications

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“…Additionally, these authors found that patients with persistent disease had a high pre-treatment intratumoral PMN to CD8 ratio. In line with this experimental data is the clinical observation that a high PMN to CD8 ratio was associated with worse overall survival [85]. The NET barrier at the interface of tumor cells and necrotic tissue was also noted by the previously mentioned study of Berger-Achituv et al in Ewing sarcoma biopsy samples [18].…”

Section: Nets Is Physically Blocking T-cell Infiltration To the Tmesupporting

confidence: 76%

“…These authors claimed that NETs may play a role in tumor radioresistance by blocking intratumoral CD8 T-cell infiltration post-RT. This effect was related to the clinical effect of the RT [85]. A higher intratumoral PMN to CD8 ratio was observed in RT non-responders compared to RT responders.…”

Section: Nets Is Physically Blocking T-cell Infiltration To the Tmementioning

confidence: 89%

“…NETs were found to be surrounding CD8 T-cells but not colocalizing with them. Moreover, increased intratumoral CD8 T-cell infiltration was noted in tumors of mice treated with DNAse I [85]. These authors claimed that NETs may play a role in tumor radioresistance by blocking intratumoral CD8 T-cell infiltration post-RT.…”

Section: Nets Is Physically Blocking T-cell Infiltration To the Tmementioning

confidence: 97%

“…Bilyy et al demonstrated that NETs form a barrier between necrotic and viable areas in acute abdominal inflammation [84]. In a very recent study, Surashri Shinde-Jadhav et al [85] discovered a direct link between intratumoral NETs and T-cell cytotoxicity. These authors demonstrated that NETs formed a barrier between the irradiated tumor and stroma, blocking the invasion of CD8 T-cells to TME [85].…”

Section: Nets Is Physically Blocking T-cell Infiltration To the Tmementioning

confidence: 99%

“…In a very recent study, Surashri Shinde-Jadhav et al [85] discovered a direct link between intratumoral NETs and T-cell cytotoxicity. These authors demonstrated that NETs formed a barrier between the irradiated tumor and stroma, blocking the invasion of CD8 T-cells to TME [85]. NETs were found to be surrounding CD8 T-cells but not colocalizing with them.…”

Section: Nets Is Physically Blocking T-cell Infiltration To the Tmementioning

confidence: 99%

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Neutrophil Extracellular Traps (NETs) in Cancer Invasion, Evasion and Metastasis

Demkow

2021

Cancers

123

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The present review highlights the complex interactions between cancer and neutrophil extracellular traps (NETs). Neutrophils constitute the first line of defense against foreign invaders using major effector mechanisms: phagocytosis, degranulation, and NETs formation. NETs are composed from decondensed nuclear or mitochondrial DNA decorated with proteases and various inflammatory mediators. Although NETs play a crucial role in defense against systemic infections, they also participate in non-infectious conditions, such as inflammation, autoimmune disorders, and cancer. Cancer cells recruit neutrophils (tumor-associated neutrophils, TANs), releasing NETs to the tumor microenvironment. NETs were found in various samples of human and animal tumors, such as pancreatic, breast, liver, and gastric cancers and around metastatic tumors. The role of the NETs in tumor development increasingly includes cancer immunoediting and interactions between the immune system and cancer cells. According to the accumulated evidence, NETs awake dormant cancer cells, causing tumor relapse, as well as its unconstrained growth and spread. NETs play a key regulatory role in the tumor microenvironment, such as the development of distant metastases through the secretion of proteases, i.e., matrix metalloproteinases and proinflammatory cytokines. NETs, furthermore, directly exacerbate tumor aggressiveness by enhancing cancer migration and invasion capacity. The collected evidence also states that through the induction of the high-mobility group box 1, NETs induce the epithelial to mesenchymal transition in tumor cells and, thereby, potentiate their invasiveness. NET proteinases can also degrade the extracellular matrix, promoting cancer cell extravasation. Moreover, NETs can entrap circulating cancer cells and, in that way, facilitate metastasis. NETs directly trigger tumor cell proliferation through their proteases or activating signals. This review focused on the pro-tumorigenic action of NETs, in spite of its potential to also exhibit an antitumor effect. NET components, such as myeloperoxidase or histones, have been shown to directly kill cancer cells. A better understanding of the crosstalk between cancer and NETs can help to devise novel approaches to the therapeutic interventions that block cancer evasion mechanisms and prevent metastatic spread. This review sought to provide the most recent knowledge on the crosstalk between NETs and cancer, and bring more profound ideas for future scientists exploring this field.

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Section: Nets Is Physically Blocking T-cell Infiltration To the Tmesupporting

confidence: 76%

Section: Nets Is Physically Blocking T-cell Infiltration To the Tmementioning

confidence: 89%

Section: Nets Is Physically Blocking T-cell Infiltration To the Tmementioning

confidence: 97%

Section: Nets Is Physically Blocking T-cell Infiltration To the Tmementioning

confidence: 99%

Section: Nets Is Physically Blocking T-cell Infiltration To the Tmementioning

confidence: 99%

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Neutrophil Extracellular Traps (NETs) in Cancer Invasion, Evasion and Metastasis

Demkow

2021

Cancers

123

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Liraglutide enhances the effect of checkpoint blockade in lung and liver cancers through the inhibition of neutrophil extracellular traps

et al. 2024

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Glucagon‐like peptide‐1 (GLP‐1) regulates glycemic excursions by augmenting insulin production and inhibiting glucagon secretion. Liraglutide, a long‐acting GLP‐1 analog, can improve glycemic control for treating type 2 diabetes and prevent neutrophil extravasation in inflammation. Here, we explored the role of liraglutide in the development and therapy of murine lung and liver cancers. In this study, liraglutide substantially decreased circulating neutrophil extracellular trap (NET) markers myeloperoxidase, elastase, and dsDNA in LLC and Hepa1‐6 tumor‐bearing mice. Furthermore, liraglutide downregulated NETs and reactive oxygen species (ROS) of neutrophils in the tumor microenvironment. Functionally, in vitro experiments showed that liraglutide reduced NET formation by inhibiting ROS. In addition, we showed that liraglutide enhanced the anti‐tumoral efficiency of PD‐1 inhibition in LLC and Hepa1‐6 tumor‐bearing C57BL/6 mice. However, the removal of NETs significantly weakened the antitumor efficiency of liraglutide. We further demonstrated that the long‐term antitumor CD8+ T cell responses induced by the combination therapy rejected rechallenges by respective tumor cell lines. Taken together, our findings suggest that liraglutide may promote the anti‐tumoral efficiency of PD‐1 inhibition by reducing NETs in lung and liver cancers.

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Engineering Radiosensitizer‐Based Metal‐Phenolic Networks Potentiate STING Pathway Activation for Advanced Radiotherapy

et al. 2022

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Beyond technological advances in radiotherapy, including stereotactic body radiation therapy, intensity-modulated radiotherapy, and image-guided radiotherapy, X-ray irradiation in combination with efficient radiosensitizers has also been extensively explored to reduce sideeffects of radiotherapy. [3] Radiosensitizers, chemical drugs or nanoparticles that greatly sensitize tumors to X-ray irradiation, allow improved tumor control while maintaining normal organs tolerance. [4] High-Z metals (e.g., hafnium, gold, and lanthanide elements), as efficient radiosensitizers, may interact with X-ray via several physical processes, releasing Auger electrons, Compton electrons, and photoelectrons. [5] Subsequently, these electrons interact with a water molecule to generate cytotoxic reactive oxygen species (ROS), inducing irreparable DNA lesions. [6] These processes are regarded as radiosensitization. Typically, AGulX, a first-in-class radiosensitizer composed of gadolinium nanoparticles, is currently in the clinical stage. [7] Therefore, developing novel lanthanide-doped radiosensitizers will give more chances to sensitizing radiotherapy for cancer treatment.Moreover, the immunosuppressive tumor microenvironment (TME) severely accelerates tumor radioresistance and results in depressed systemic antitumor immunity. [8] Recently, researchers have demonstrated that ionizing radiation can evoke type I interferon (IFN)-associated adaptive immunity based on stimulator of interferon genes (STING) proteins activation. [9] When undergoing X-ray irradiation, damaged tumor DNA escapes from the nucleus to the cytosol. [10] The as-released cytosolic dsDNA can be sensed by cyclic guanosine monophosphate (GMP)-adenosine monophosphate (AMP) synthase (cGAS), which catalyzes adenylate triphosphate and guanosine triphosphate into 2′,3′-cyclic GMP-AMP and finally activates STING. Such activated STING further binds and activates the tank-binding kinase 1 (TBK1) that phosphorylates the interferon regulatory factor 3 (IRF3), elevating the production of type I IFN. The type I IFN signaling potentiates tumor-specific antigen presentation on dendritic cells (DCs) and cross-prime antitumor T cells for adaptive immunity. Emerging evidence Radiotherapy, a mainstay of first-line cancer treatment, suffers from its high-dose radiation-induced systemic toxicity and radioresistance caused by the immunosuppressive tumor microenvironment. The synergy between radiosensitization and immunomodulation may overcome these obstacles for advanced radiotherapy. Here, the authors propose a radiosensitization cooperated with stimulator of interferon genes (STING) pathway activation strategy by fabricating a novel lanthanide-doped radiosensitizer-based metal-phenolic network, NaGdF 4 :Nd@NaLuF 4 @PEG-polyphenol/Mn (DSPM). The amphiphilic PEG-polyphenol successfully coordinates with NaGdF 4 :Nd@NaLuF 4 (radiosensitizer) and Mn 2+ via robust metal-phenolic coordination. After cell internalization, the pH-responsive disassembly of DSPM triggers the release of their payloads...

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Role of neutrophil extracellular traps in radiation resistance of invasive bladder cancer

Cited by 127 publications

References 67 publications

Neutrophil Extracellular Traps (NETs) in Cancer Invasion, Evasion and Metastasis

Neutrophil Extracellular Traps (NETs) in Cancer Invasion, Evasion and Metastasis

Liraglutide enhances the effect of checkpoint blockade in lung and liver cancers through the inhibition of neutrophil extracellular traps

Engineering Radiosensitizer‐Based Metal‐Phenolic Networks Potentiate STING Pathway Activation for Advanced Radiotherapy

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