ArticleJCI insight2018
Continuous treatment with IL-15 exhausts human NK cells via a metabolic defect.
Article in JCI insight, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 186 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
186 citing papers in PubMed, 253 citations in OpenAlex.
- Use of CAR-Transduced Natural Killer Cells in CD19-Positive Lymphoid Tumors.The New England journal of medicine · 2020Trial
- IL-15 trans-presentation at the innate-adaptive interface: mechanisms and translation in cancer immunotherapy.Oncoimmunology · 2026Review
- Next-generation natural killer cell therapy: bench to bedside and beyond.Signal transduction and targeted therapy · 2026Review
- IL-15 boosts mesothelin- and CD70-CAR NK cell potency in PDAC without added benefit from dual targeting.Molecular therapy. Oncology · 2026Article
- Review
- The CREM-IL-15 axis: decoding the persistence-exhaustion paradox in NK cell immunotherapy.Cancer immunology, immunotherapy : CII · 2026Review
- HIV tri-specific killer engagers directly enhance NK cell function and safely expand NK cells in vivo.Cell reports. Medicine · 2026Article
- ITPKB is a conserved regulator of natural killer cell desensitization/education that constrains antitumor immunity.bioRxiv : the preprint server for biology · 2026Article
- PEG-RLI: A Long-Acting IL-15 Agonist That Produces Massive Levels of CD8Pharmaceutics · 2026Article
- Multifunctional-engineered NK cells overcome tumor immunosuppression by combining PD-L1 and HLA-E targeting and endogenous IL15 production.Signal transduction and targeted therapy · 2026Article
- Article
- Autophagy supports the storage of lytic granules in human NK cells.Cell death & disease · 2026Article
- PTPN1/PTPN2 inhibition improves NK cancer therapy by enhancing IL-2 and mitigating TGFβ1 responses.EMBO reports · 2026Article
- Constitutive RLI Armoring Enhances CAR-NK Cell Effector Functions but Causes Lethal Toxicity In Vivo.International journal of molecular sciences · 2026Article
- Review
- Metabolic licensing and restriction of innate immunity in the tumor microenvironment.Frontiers in immunology · 2026Review
- Advances in IL-15-Based Cancer Immunotherapy and Divergent Immunological Effects of IL-2 and IL-15 Signaling via the Shared IL-2Rβγ Receptor.Frontiers in immunology · 2026Review
- Interaction of CD99 and its ligands regulates immunoregulatory pathways in NK cells.Frontiers in immunology · 2026Article
- A Pilot Study of COVID-19 Outcomes in People Living with HIV in Tatarstan.International journal of molecular sciences · 2025Article
- Article
126 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
10 authors at 2 institutions in 1 country.
Funding
Abstract
NK cell-based immunotherapies have been gaining traction in the clinic for treatment of cancer. IL-15 is currently being used in number of clinical trials to improve NK cell expansion and function. The objective of this study is to evaluate the effect of repetitive IL-15 exposure on NK cells. An in vitro model in which human NK cells are continuously (on on on) or intermittently (on off on) treated with IL-15 was used to explore this question. After treatment, cells were evaluated for proliferation, survival, cell cycle gene expression, function, and metabolic processes. Our data indicate that continuous treatment of NK cells with IL-15 resulted in decreased viability and a cell cycle arrest gene expression pattern. This was associated with diminished signaling, decreased function both in vitro and in vivo, and reduced tumor control. NK cells continuously treated with IL-15 also displayed a reduced mitochondrial respiration profile when compared with NK cells treated intermittently with IL-15. This profile was characterized by a decrease in the spare respiratory capacity that was dependent on fatty acid oxidation (FAO). Limiting the strength of IL-15 signaling via utilization of an mTOR inhibitor rescued NK cell functionality in the group continuously treated with IL-15. The findings presented here show that human NK cells continuously treated with IL-15 undergo a process consistent with exhaustion that is accompanied by a reduction in FAO. These findings should inform IL-15-dosing strategies in NK cell cancer immunotherapeutic settings.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.