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Aged neutrophils fuel tumor progression: Good cells gone bad
Author(s) -
Mittmann Laura Alice,
Schaubaecher Johanna B.,
Hennel Roman,
Lauber Kirsten,
Uhl Bernd,
Reichel Christoph A.
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2019.33.1_supplement.542.11
Subject(s) - inflammasome , aim2 , immune system , hmgb1 , cancer research , inflammation , immunology , tumor progression , innate immune system , cancer cell , neutrophil extracellular traps , cancer , biology , medicine
Neutrophilic granulocytes (neutrophils) represent the first immune cells recruited to the site of injury or infection. Beyond their well‐established role in inflammatory pathologies, these leukocytes are increasingly recognized to modulate initiation, progression, and metastasis of cancer. Recently, ageing of mature neutrophils in the circulation has been identified to be critical for proper immune responses in inflammatory scenarios. The fate and function of aged neutrophils in malignant disorders, however, remain elusive. Here, we demonstrate for the first time that particularly aged neutrophils are recruited to malignant tumors as evidenced in heterotopic (multi‐channel in vivo microscopy) and orthotopic mouse models (multi‐channel flow cytometry) of mammary or head and neck carcinoma. Mechanistically, tumor‐released damage associated molecular patterns (DAMPs) including S100A8/9 and uric acid, but not high mobility group box 1 (HMGB1), initiate responses of these ‘experienced’ immune cells by activating the multimeric intracellular NLRP3 inflammasome (but not NLRP1, AIM2, or NLRC4 inflammasomes) in peritumoral macrophages. This leads to the release of cytokines that, in turn, activate microvascular endothelial cells, ultimately promoting the trafficking of aged neutrophils to neoplastic lesions. Most interestingly, aged neutrophils were found to exhibit a pro‐tumorigenic ‘N2’ phenotype. Accordingly, blockade of NLRP3 activation almost completely abolished responses of aged neutrophils in the peritumoral microvasculature as well as the subsequent infiltration of these immune cells into malignant lesions. Concomitantly, NLRP3 inhibition severely compromised tumor growth to the level of neutrophil‐depleted animals in these experiments, but did not directly affect the proliferation of cancer cells in vitro . Thus, our experimental data uncover a previously unappreciated role of aged neutrophils as potent regulators of tumor progression. Interfering with the recruitment of these immune cells to malignant lesions might emerge as a promising immunotherapeutic strategy to prevent advanced stages of cancer. Support or Funding Information This study was supported by Deutsche Forschungsgemeinschaft (DFG), Sonderforschungsbereich (SFB) 914 . This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .