Immune Cell Function and Interaction
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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.
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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.
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@article{Kennedy2024Metabolic,
title = {Metabolic programs drive function of therapeutic NK cells in hypoxic tumor environments},
author = {Philippa R Kennedy and Upasana Sunil Arvindam and Shee Kwan Phung and Brianna Ettestad and Xueyang Feng and Yunmin Li and Quinlan M. Kile and Peter Hinderlie and Melissa Khaw and Rih‐Sheng Huang and Marissa Kaufman and Patrycja Puchalska and Amanda J. Russell and Jonah Z. Butler and Lucas Abbott and P. D. McClure and Xianghua Luo and Qiping Lu and Bruce R. Blazar and Peter A. Crawford and James Lim and Jeffrey S. Miller and Martin Felices},
journal = {Science Advances},
year = {2024},
doi = {10.1126/sciadv.adn1849},
url = {https://doi.org/10.1126/sciadv.adn1849}
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