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.
Bibliographical noteFunding Information:
This study was supported by the National Research Foundation (NRF) grants [NRF-2016M3A9B6948342, NRF-2018M3A9D3079288 and NRF-2020R1A2C2103061]. H. Park was supported by NRF [NRF-2013M3A9D3046248, NRF-2018R1A4A1025985]. M.H.S. was supported by NRF [NRF-2018R1D1A1B07041442] and a Korea University Grant.
Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland.
- NK cells
- Tumor microenvironment