Loss of HIF-1 alpha in natural killer cells inhibits tumour growth by stimulating non-productive angiogenesis

Ewelina Krzywinska (1, 2) , Chahrazade Kantari-Mimoun (3) , Yann Kerdiles (4) , Michal Sobecki (5) , Takayuki Isagawa , Dagmar Gotthardt , Magali Castells , Johannes Haubold , Corinne Millien (6) , Thomas Viel (6) , Bertrand Tavitian (6, 7, 8) , Norihiko Takeda , Joachim Fandrey (9) , Eric Vivier (4) , Veronika Sexl (10) , Christian Stockmann

1 Cellules souches normales et cancéreuses
2 IRB - Institut de recherche en biothérapie
3 IC UM3 (UMR 8104 / U1016) - Institut Cochin
4 CIML - Centre d'Immunologie de Marseille - Luminy
5 Department of Medicinal Chemistry and Microbiology
6 PARCC - UMR-S U970 - Paris-Centre de Recherche Cardiovasculaire
7 UPD5 - Université Paris Descartes - Paris 5
8 HEGP - Hôpital Européen Georges Pompidou [APHP]
9 Institut Physiology, Essen
10 Medizinische Universität Wien = Medical University of Vienna

Productive angiogenesis, a prerequisite for tumour growth, depends on the balanced release of angiogenic and angiostatic factors by different cell types within hypoxic tumours. Natural killer (NK) cells kill cancer cells and infiltrate hypoxic tumour areas. Cellular adaptation to low oxygen is mediated by Hypoxia-inducible factors (HIFs). We found that deletion of HIF-1 alpha in NK cells inhibited tumour growth despite impaired tumour cell killing. Tumours developing in these conditions were characterised by a high-density network of immature vessels, severe haemorrhage, increased hypoxia, and facilitated metastasis due to non-productive angiogenesis. Loss of HIF-1 alpha in NK cells increased the bioavailability of the major angiogenic cytokine vascular endothelial growth factor (VEGF) by decreasing the infiltration of NK cells that express angiostatic soluble VEGFR-1. In summary, this identifies the hypoxic response in NK cells as an inhibitor of VEGF-driven angiogenesis, yet, this promotes tumour growth by allowing the formation of functionally improved vessels.

Domaines: Immunologie

Ewelina Krzywinska, Chahrazade Kantari-Mimoun, Yann Kerdiles, Michal Sobecki, Takayuki Isagawa, et al.. Loss of HIF-1 alpha in natural killer cells inhibits tumour growth by stimulating non-productive angiogenesis. Nature Communications, 2017, 8 (1), ⟨10.1038/s41467-017-01599-w⟩. ⟨hal-01764694⟩