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Relief of tumor hypoxia unleashes the tumoricidal potential of neutrophils
Karim Mahiddine, … , Clifford A. Lowell, Adrian Erlebacher
Karim Mahiddine, … , Clifford A. Lowell, Adrian Erlebacher
Published October 10, 2019
Citation Information: J Clin Invest. 2020;130(1):389-403. https://doi.org/10.1172/JCI130952.
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Research Article Immunology Oncology

Relief of tumor hypoxia unleashes the tumoricidal potential of neutrophils

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Abstract

Polymorphonuclear neutrophils (PMNs) are increasingly recognized to influence solid tumor development, but why their effects are so context dependent and even frequently divergent remains poorly understood. Using an autochthonous mouse model of uterine cancer and the administration of respiratory hyperoxia as a means to improve tumor oxygenation, we provide in vivo evidence that hypoxia is a potent determinant of tumor-associated PMN phenotypes and direct PMN–tumor cell interactions. Upon relief of tumor hypoxia, PMNs were recruited less intensely to the tumor-bearing uterus, but the recruited cells much more effectively killed tumor cells, an activity our data moreover suggested was mediated via their production of NADPH oxidase–derived reactive oxygen species and MMP-9. Simultaneously, their ability to promote tumor cell proliferation, which appeared to be mediated via their production of neutrophil elastase, was rendered less effective. Relieving tumor hypoxia thus greatly improved net PMN-dependent tumor control, leading to a massive reduction in tumor burden. Remarkably, this outcome was T cell independent. Together, these findings identify key hypoxia-regulated molecular mechanisms through which PMNs directly induce tumor cell death and proliferation in vivo and suggest that the contrasting properties of PMNs in different tumor settings may in part reflect the effects of hypoxia on direct PMN–tumor cell interactions.

Authors

Karim Mahiddine, Adam Blaisdell, Stephany Ma, Amandine Créquer-Grandhomme, Clifford A. Lowell, Adrian Erlebacher

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Figure 5

Relief of tumor hypoxia alters the transcriptional signature of tumor-associated PMNs and their production of active MMP-9 and NE.

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Relief of tumor hypoxia alters the transcriptional signature of tumor-as...
(A) Volcano plot showing the 423 differentially expressed protein-coding genes (FDR < 0.05) in PMNs isolated from PRPL mice housed under normoxia versus hyperoxia conditions (n = 3 per group). We excluded genes whose maximal average normalized reads in both of the 2 groups was less than 50. (B) Volcano plot of this same gene set but with the x axis showing the log10 of the absolute difference in mean normalized reads, to accentuate genes that are more differentially expressed in absolute terms. (C–E) Gelatin and casein zymograms performed on uterine extracts. Each lane represents a different mouse. Equal protein amounts were loaded per well. (F and G) Quantification of MMP-9 and NE band intensities. Graphs also show the mean ± SEM. **P < 0.01 by 2-tailed Mann-Whitney U test. In addition to the 2 gels shown (C and E), these data came from extracts run in 2 additional gelatin zymograms and 1 additional casein zymogram.
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