Authors: Philippa R. Kennedy, Upasana Sunil Arvindam, Shee Kwan Phung, Brianna Ettestad, Xueyang Feng, Yunmin Li, Quinlan M. Kile, Peter Hinderlie, Melissa Khaw, Rih-Sheng Huang, Marissa Kaufman, Patrycja Puchalska, Amanda Russell, Jonah Butler, Lucas Abbott, Paul McClure, Xianghua Luo, Quynhanh T. Lu, Bruce R. Blazar, Peter A. Crawford, James Lim, Jeffrey S. Miller, Martin Felices
Published: 2024-10-30
Source: Full article
Limited oxygen (hypoxia) in solid tumors poses a challenge to successful immunotherapy with natural killer (NK) cells. NK cells have impaired cytotoxicity when cultured in hypoxia (1% oxygen) but not physiologic (>5%) or atmospheric oxygen (20%). We found that changes to cytotoxicity were regulated at the transcriptional level and accompanied by metabolic dysregulation. Dosing with interleukin-15 (IL-15) enhanced NK cell cytotoxicity in hypoxia, but preactivation with feeder cells bearing IL-21 and 4-1BBL was even better. Preactivation resulted in less perturbed metabolism in hypoxia; greater resistance to oxidative stress; and no hypoxia-induced loss of transcription factors (T-bet and Eomes), activating receptors, adhesion molecules (CD2), and cytotoxic proteins (TRAIL and FasL). There remained a deficit in CD122/IL-2Rβ when exposed to hypoxia, which affected IL-15 signaling. However, tri-specific killer engager molecules that deliver IL-15 in the context of anti-CD16/FcγRIII were able to bypass this deficit, enhancing cytotoxicity of both fresh and preactivated NK cells in hypoxia.