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NETosis in cancer: a critical analysis of the impact of cancer on neutrophil extracellular trap (NET) release in lung cancer patients vs. mice

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Abstract

Neutrophils play a major role in tumor biology. Among other functions, neutrophils can release extracellular traps (NETs), mesh-like structures of decondensed chromatin fibers, in a process termed NETosis. Originally characterized as an antimicrobial mechanism, NETosis has been described in cancer, but cancer-related predisposition is not clear. In the current study, we investigated the predisposition of circulating neutrophils to release NETs in lung cancer and the impact of G-CSF on this function, comparing circulating neutrophils isolated from cancer patients to the LLC and AB12 mouse models. We find that neutrophils from both healthy donors and cancer patients display high NETotic potential, with 30–60% of cells undergoing NETosis upon PMA stimulation. In contrast, neutrophils isolated from tumor-bearing mice displayed only 4–5% NETotic cells, though significantly higher than naive controls (1–2%). Despite differential mechanisms of activation described, Ionomycin and PMA mainly triggered suicidal rather than vital NETosis. G-CSF secreting tumors did not increase NETotic rates in murine neutrophils, and direct G-CSF stimulation did not promote their NET release. In contrast, human neutrophils strongly responded to G-CSF stimulation resulting also in a higher response to PMA + G-CSF stimulation. Our data show clear differences in NETotic potentials between human and murine neutrophils. We do not find a predisposition of neutrophils to release NETs in lung cancer patients compared to healthy controls, whereas cancer may modulate neutrophils' NETotic potential in mice. G-CSF secreted from tumors differentially affects murine and human NETosis in cancer. These important differences should be considered in future studies of NETosis in cancer.

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Abbreviations

CitH3:

Citrullinated histone3

COPD:

Chronic obstructive pulmonary disease

EDTA:

Ethylenediaminetetraacetic acid 

fMLP:

N-Formylmethionyl-leucyl-phenylalanine

G-CSF:

Granulocyte colony stimulating factor

HDN:

High density neutrophils

HMGB1:

High mobility group box1

LDN:

Low density neutrophils

LLC:

Lewis lung carcinoma

LPS:

Lipopolysaccharide

MPO:

Myeloperoxidase

NET:

Neutrophil extracellular traps

PMA:

Phorbol myristate acetate

ROS:

Reactive oxygen species

TAN:

Tumor-associated neutrophils

TGFβ:

Transforming growth factor beta

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Acknowledgements

This work was kindly backed by the European Cooperation in Science and Technology (COST) Action BM1404 Mye-EUNITER.

Funding

This work was supported by grants from the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) in cooperation with the Israeli Ministry of Science and Technology (MOST) CA2656 (to Zvi G Fridlender), the Naor Sasson fund, and the Israel Lung Association.

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Authors and Affiliations

  1. Institute of Pulmonary Medicine, Hebrew University Hadassah Medical Center, POB 12000, 9112001, Jerusalem, Israel

    Ludovica Arpinati, Merav E. Shaul, Naomi Kaisar-Iluz, Shira Mali, Sojod Mahroum & Zvi G. Fridlender

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  1. Ludovica Arpinati
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  2. Merav E. Shaul
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Contributions

Study and experimental design: LA, MES and ZGF; sample collection and processing: LA, NKa-I, and SM. Data analysis and interpretation: LA, MS, NK-I, SM, SM. Writing and editing: LA, MES and ZGF.

Corresponding author

Correspondence to Zvi G. Fridlender.

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Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval and ethical standards

All procedures involving human participants were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. The study was approved by the Hadassah Medical Center Institutional Helsinki Review Board, approval number: 0615-16-HMO (Nov 4th 2016). All procedures involving animals were in accordance with the ethical standards of the Animal Care and Research Committee of the Hebrew University School of Medicine; study approval number 14697-5 (August 8th 2017).

Informed consent

Written informed consent was obtained from all participants before blood samples were taken. Patients and heatly volunteers consented to the use of blood sample for research purposes and for publication.

Animal sources

C57BL/6 mice and Balb/C mice, 6–8 week of age, 20–25 g weight, were purchased from Harlan Laboratories (Jerusalem, Israel) and were housed under specific pathogen-free (SPF) conditions at the Hebrew University School of Medicine Animal Resource Center.

Cell line authentication

Murine LLC cell line was purchased from the American Type Culture Collection (ATCC, Manassas, VA). AB12, a murine malignant mesothelioma cell line, derived from an asbestos-induced tumor in a Balb/C mouse, was kindly provided by Prof. Steven Albelda, University of Pennsylvania, PA, USA. The cell lines were expanded and cryopreserved according to ATCC guidelines, and regularly checked for mycobacteria.

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This paper is based on a presentation given at the Sixth International Conference on Cancer Immunotherapy and Immunomonitoring (CITIM 2019), held in Tbilisi, Georgia, 29th April–2nd May 2019. It is part of a series of CITIM 2019 papers in Cancer Immunology, Immunotherapy.

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Arpinati, L., Shaul, M.E., Kaisar-Iluz, N. et al. NETosis in cancer: a critical analysis of the impact of cancer on neutrophil extracellular trap (NET) release in lung cancer patients vs. mice. Cancer Immunol Immunother 69, 199–213 (2020). https://doi.org/10.1007/s00262-019-02474-x

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