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PMID: 29415897 Published · epublish English Journal Article Research Support, N.I.H., Extramural Research Support, U.S. Gov't, Non-P.H.S.

Continuous treatment with IL-15 exhausts human NK cells via a metabolic defect.

JCI insight ·Vol. 3 ·No. 3 ·2018-00-08

Felices M, Lenvik AJ, McElmurry R, Chu S, Hinderlie P, Bendzick L, Geller MA, Tolar J, Blazar BR, Miller JS

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.

Keywords
Cytokines Fatty acid oxidation Immunology NK cells
MeSH Terms
Animals Blood Buffy Coat/cytology Cell Line, Tumor Clinical Trials as Topic Fatty Acids/metabolism Humans Immunotherapy/methods Interleukin-15/metabolism Killer Cells, Natural/drug effects,immunology,metabolism,transplantation Mice Neoplasms/immunology,metabolism,pathology,therapy Oxidation-Reduction/drug effects Recombinant Proteins/administration & dosage,adverse effects Signal Transduction/drug effects,immunology Sirolimus/pharmacology TOR Serine-Threonine Kinases/antagonists & inhibitors,immunology,metabolism Whole-Body Irradiation Xenograft Model Antitumor Assays
Chemicals
Fatty Acids IL15 protein, human Interleukin-15 Recombinant Proteins MTOR protein, human TOR Serine-Threonine Kinases Sirolimus
Authors & Affiliations
10 authors, click to expand affiliations / ORCID
Felices Martin
Department of Medicine, Division of Hematology, Oncology, and Transplantation.
Lenvik Alexander J
Department of Medicine, Division of Hematology, Oncology, and Transplantation.
McElmurry Ron
Department of Pediatrics, and.
Chu Sami
Department of Medicine, Division of Hematology, Oncology, and Transplantation.
Hinderlie Peter
Department of Medicine, Division of Hematology, Oncology, and Transplantation.
Bendzick Laura
Department of Obstetrics, Gynecology and Women's Health, Division of Gynecologic Oncology, University of Minnesota, Minneapolis, Minnesota, USA.
Geller Melissa A
Department of Obstetrics, Gynecology and Women's Health, Division of Gynecologic Oncology, University of Minnesota, Minneapolis, Minnesota, USA.
Tolar Jakub
Department of Pediatrics, and.
Blazar Bruce R
Department of Pediatrics, and.
Miller Jeffrey S
Department of Medicine, Division of Hematology, Oncology, and Transplantation.
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Article Info
Journal
JCI insight
Abbr.
JCI Insight
ISSN
2379-3708
DOI
10.1172/jci.insight.96219
Published
2018-00-08
Epub
2018-00-08
Language
English
Region
United States
NLM ID
101676073
PMCID
PMC5821201
Subset
IM
Grants
NCI NIH HHS · P01 CA065493 · United States
NHLBI NIH HHS · R01 HL118979 · United States
NHLBI NIH HHS · R01 HL122216 · United States
NCI NIH HHS · R35 CA197292 · United States
NCI NIH HHS · P01 CA111412 · United States
External Links
PubMed source DOI: 10.1172/jci.insight.96219 PMC Full Text View journal details
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