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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 3

PMNs simultaneously promote and inhibit PRPL tumor growth, with the 2 effects divergently influenced by tumor hypoxia.

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PMNs simultaneously promote and inhibit PRPL tumor growth, with the 2 ef...
PRPL (A and C) and PRPL-Csf3r–/– (B and D) mice were sacrificed on P28. (A and B) E-Cad/Ly6G double immunostaining to illustrate PMN-dependent tumor cell sloughing and denudation of the uterine stroma (see also ref. 5). Asterisks indicate intraluminal tumor cell debris admixed with PMNs. The arrows demarcate the nearby denuded endometrial surface. s, endometrial stroma; lu, uterine lumen. (C and D) α6/CK8 double immunostaining to illustrate PMN-dependent loss of α6 integrin from the basolateral tumor cell membrane (see also ref. 5). In the PRPL mouse (C), note the epithelial/stromal interface completely devoid of α6 staining (yellow arrowheads) and the intermittent α6 staining at other locations along this interface (white arrowheads). Blood vessels (bv) remain α6+. In the PRPL-Csf3r–/– mouse (D), α6 staining is largely continuous along the epithelial/stromal interface (see Supplemental Figure 5, A–D, for additional representative images). (E and F) Representative E-Cad–stained uterine sections of PRPL mice housed under normoxia and hyperoxia conditions (n = 6 mice/group) to illustrate sloughed tumor cells (asterisks) and denuded endometrial surfaces (arrows). (G and H) Tumor cell sloughing (percentage intraluminal debris of total tumor area (G) and percentage of denuded endometrial surface (H), determined from E-Cad–stained sections. (I) Percentage of tumor epithelial surface with basolateral α6 integrin staining, determined from α6/CK8–stained sections. (J) Tumor cell proliferation, as measured by phospho–histone H3 (p-H3) immunostaining to identify mitotic cells. Graphs also show the mean ± SEM. **P < 0.01 by 2-tailed Mann-Whitney U test.
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