Heterogenous presence of neutrophil extracellular traps in human solid tumours is partially dependent on <scp>IL</scp>‐8

Andrea, Carlos de; Ochoa, María C.; Villalba-Esparza, María; Teijeira, Álvaro; Schalper, Kurt A.; Abengozar-Muela, Marta; Eguren-Santamaría, Iñaki; Sainz, Cristina; Sánchez-Gregorio, Sandra; Garasa, Saray; Ariz, Mikel; Ortiz‐de‐Solórzano, Carlos; Rodríguez-Ruiz, María E.; Perez-Gracia, José Luis; Lozano, María Dolores; Echeveste, José; Sanmamed, Miguel F.; Melero, Ignacio

doi:10.1002/path.5753

Cited by 69 publications

(66 citation statements)

References 51 publications

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“…Since NET formation also primed the premetastatic niche and promoted tumor dissemination in a lung metastasis model of breast cancer (41), inhibition of NET hampered the progression of established tumors and impaired metastasis (40). Concordantly, an increased NET area was detected in relapsed breast cancer specimens in our cohort (42). Thus, we could anticipate that several NET inhibitors currently tested in the clinic including PAD4 antagonists, IL-8 neutralizing antibodies (43), and CXCR2 inhibitors could also impact LRF.…”

Section: Clinical Relevance Of Enpp1 and Net In Lrfsupporting

confidence: 61%

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Tumor ENPP1 (CD203a)/Haptoglobin Axis Exploits Myeloid-Derived Suppressor Cells to Promote Post-Radiotherapy Local Recurrence in Breast Cancer

et al. 2022

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Locoregional failure (LRF) in breast cancer patients post-surgery and post-irradiation (IR) is linked to a dismal prognosis. In a refined new model, we identified Enpp1 (Ectonucleotide pyrophosphatase /phosphodiesterase 1/CD203a) to be closely associated with LRF. Enpp1 high circulating tumor cells (CTC) contribute to relapse by a self-seeding mechanism. This process requires the infiltration of PMN-MDSC and neutrophil extracellular traps (NET) formation. Genetic and pharmacological Enpp1 inhibition or NET blockade extend relapse-free survival. Furthermore, in combination with fractionated irradiation (FD), Enpp1 abrogation obliterates LRF.Mechanistically, Enpp1-generated adenosinergic metabolites enhance Haptoglobin (Hp) expression.This inflammatory mediator elicits myeloid invasiveness and promotes NET formation. Accordingly, a significant increase in ENPP1 and NET formation is detected in relapsed human breast cancer tumors. Moreover, high ENPP1 or HP levels are associated with poor prognosis. These findings unveil the ENPP1/HP axis as an unanticipated mechanism exploited by tumor cells linking inflammation to immune remodeling favoring local relapse.

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Section: Clinical Relevance Of Enpp1 and Net In Lrfsupporting

confidence: 61%

“…Software, an open-source Java-based image processing software. Measurement workflow and scoring have been previously described (42). In short, neutrophils were identified by the co-staining with CD15 and MPO.…”

Section: And Imagejmentioning

confidence: 99%

Tumor ENPP1 (CD203a)/Haptoglobin Axis Exploits Myeloid-Derived Suppressor Cells to Promote Post-Radiotherapy Local Recurrence in Breast Cancer

et al. 2022

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“…A further study demonstrated that CXCL8 induced tumor-associated neutrophil and granulocytic MDSC extrusion of NETs, which shield tumor cells from contact with CD8 + T cells and limit the anti-PD-1 immune response to cancer [ 98 ]. Conclusive evidence showed that multiple human cancer types contain NETs, which had a positive association with CXCL8 and reduced CD8 + T-cell infiltration [ 99 ]. Tumorous CXCL8 mediates increased NETs formation in the TME, promoting colorectal cancer liver metastasis [ 100 ].…”

Section: Cxcl8-cxcr1/2 Signaling Pathwaymentioning

confidence: 99%

Roles of the CXCL8-CXCR1/2 Axis in the Tumor Microenvironment and Immunotherapy

Han

Yang

et al. 2021

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In humans, Interleukin-8 (IL-8 or CXCL8) is a granulocytic chemokine with multiple roles within the tumor microenvironment (TME), such as recruiting immunosuppressive cells to the tumor, increasing tumor angiogenesis, and promoting epithelial-to-mesenchymal transition (EMT). All of these effects of CXCL8 on individual cell types can result in cascading alterations to the TME. The changes in the TME components such as the cancer-associated fibroblasts (CAFs), the immune cells, the extracellular matrix, the blood vessels, or the lymphatic vessels further influence tumor progression and therapeutic resistance. Emerging roles of the microbiome in tumorigenesis or tumor progression revealed the intricate interactions between inflammatory response, dysbiosis, metabolites, CXCL8, immune cells, and the TME. Studies have shown that CXCL8 directly contributes to TME remodeling, cancer plasticity, and the development of resistance to both chemotherapy and immunotherapy. Further, clinical data demonstrate that CXCL8 could be an easily measurable prognostic biomarker in patients receiving immune checkpoint inhibitors. The blockade of the CXCL8-CXCR1/2 axis alone or in combination with other immunotherapy will be a promising strategy to improve antitumor efficacy. Herein, we review recent advances focusing on identifying the mechanisms between TME components and the CXCL8-CXCR1/2 axis for novel immunotherapy strategies.

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“…IL-8 is increased in breast cancer tissues compared to adjacent normal breast tissues [ 31 ]. IL-8 secreted from tumors promotes the release of NETs [ 32 , 33 ]. Furthermore, IL-8 is positively correlated with NETs in non-small cell lung cancer (NSCLC) and melanoma [ 32 ].…”

Section: Molecular Pathway Of Netosis Stimulated By Various Agonistsmentioning

confidence: 99%

“…IL-8 secreted from tumors promotes the release of NETs [ 32 , 33 ]. Furthermore, IL-8 is positively correlated with NETs in non-small cell lung cancer (NSCLC) and melanoma [ 32 ]. IL-8 can easily bind with C-X-C motif chemokine receptor 1 (CXCR1) and C-X-C motif chemokine receptor 2 (CXCR2) [ 34 ].…”

Section: Molecular Pathway Of Netosis Stimulated By Various Agonistsmentioning

confidence: 99%

The regulatory mechanism of neutrophil extracellular traps in cancer biological behavior

et al. 2021

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As the predominant host defense against pathogens, neutrophil extracellular traps (NETs) have attracted increasing attention due to their vital roles in infectious inflammation in the past few years. Interestingly, NETs also play important roles in noninfectious conditions, such as rheumatism and cancer. The process of NETs formation can be regulated and the form of cell death accompanied by the formation of NETs is regarded as “NETosis”. A large amount of evidence has confirmed that many stimuli can facilitate the release of NETs from neutrophils. Furthermore, it has been illustrated that NETs promote tumor growth and progression via many molecular pathways. Meanwhile, NETs also can promote metastasis in many kinds of cancers based on multiple studies. In addition, some researchs have found that NETs can promote coagulation and cancer-associated thrombosis. In the present review, it will highlight how NETosis, which is stimulated by various stimuli and signaling pathways, affects cancer biological behaviors via NETs. Given their crucial roles in cancer, NETs will become possible therapeutic targets for inhibiting proliferation, metastasis and thrombosis in cancer patients.

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Heterogenous presence of neutrophil extracellular traps in human solid tumours is partially dependent on IL‐8

Abstract: Myers-Squibb, Agenus and Torque Therapeutics. All other authors declared no conflicts of interest.

Cited by 69 publications

References 51 publications

Tumor ENPP1 (CD203a)/Haptoglobin Axis Exploits Myeloid-Derived Suppressor Cells to Promote Post-Radiotherapy Local Recurrence in Breast Cancer

Tumor ENPP1 (CD203a)/Haptoglobin Axis Exploits Myeloid-Derived Suppressor Cells to Promote Post-Radiotherapy Local Recurrence in Breast Cancer

Roles of the CXCL8-CXCR1/2 Axis in the Tumor Microenvironment and Immunotherapy

The regulatory mechanism of neutrophil extracellular traps in cancer biological behavior

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