Hypoxia-driven hif-1α activation reprograms pre-activated nk cells towards highly potent effector phenotypes via erk/stat3 pathways

Seon Ah Lim, Yunwon Moon, Min Hwa Shin, Tae Jin Kim, Sehyun Chae, Cassian Yee, Daehee Hwang, Hyunsung Park, Kyung Mi Lee

Research output: Contribution to journalArticlepeer-review

10 Citations (Scopus)

Abstract

NK cells are the predominant innate lymphocyte subsets specialized to kill malignant tumor cells. In patients with advanced cancer, hypoxic stress shapes NK cells toward tumor-resistant and im-munosuppressive phenotypes, hence a strategy to restore NK function is critical for successful tumor immunotherapy. Here, we present evidence that pre-activation and subsequent HIF-1α-dependent metabolic shift of NK cells from oxidative phosphorylation into glycolysis are keys to overcome hypoxia-mediated impairment in NK cell survival, proliferation, and tumor cytotoxicity. Specifically, exposing NK cells to 7–9 days of normoxic culture followed by a pO2 of 1.5% hypoxia led to a highly potent effector phenotype via HIF-1α stabilization and upregulation of its target genes, BNIP3, PDK1, VEGF, PKM2, and LDHA. RNA sequencing and network analyses revealed that concomitant reduc-tion of p21/p53 apoptotic pathways along with upregulation of cell cycle-promoting genes, CCNE1, CDC6, CDC20, and downregulation of cell cycle-arrest genes, CDKN1A, GADD45A, and MDM2 were accountable for superior expansion of NK cells via ERK/STAT3 activation. Furthermore, HIF-1α-dependent upregulation of the NKp44 receptor in hypoxia-exposed NK cells resulted in increased killing against K562, CEM, and A375 tumor targets both in-vitro and in-vivo tumor clearance assays. Therefore, hypoxic exposure on pre-activated proliferating NK cells triggered HIF-1α-dependent pathways to initiate coordinated regulation of cell cycle, apoptosis, and cytotoxicity at the global.

Original languageEnglish
Article number1904
JournalCancers
Volume13
Issue number8
DOIs
Publication statusPublished - 2021 Apr 2

Keywords

  • HIF-1/ERK/STAT3
  • Hypoxia
  • NK cells
  • Tumor microenvironment

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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