Cytokine-induced memory-like natural killer cells have enhanced function, proliferation, and in vivo expansion against ovarian cancer cells.
Animals
Carcinoma, Ovarian Epithelial
/ immunology
Cell Line, Tumor
Cell Proliferation
/ drug effects
Cytokine-Induced Killer Cells
/ immunology
Female
Humans
Immunologic Memory
/ immunology
Immunotherapy, Adoptive
/ methods
Interferon-gamma
/ biosynthesis
Interleukin-12
/ immunology
Interleukin-15
/ immunology
Interleukin-18
/ immunology
Interleukins
/ immunology
Killer Cells, Natural
/ drug effects
Lymphocyte Activation
/ drug effects
Mice
Recombinant Proteins
/ immunology
Tumor Necrosis Factor-alpha
/ biosynthesis
Xenograft Model Antitumor Assays
Journal
Gynecologic oncology
ISSN: 1095-6859
Titre abrégé: Gynecol Oncol
Pays: United States
ID NLM: 0365304
Informations de publication
Date de publication:
04 2019
04 2019
Historique:
received:
26
09
2018
revised:
12
12
2018
accepted:
03
01
2019
pubmed:
20
1
2019
medline:
14
5
2019
entrez:
20
1
2019
Statut:
ppublish
Résumé
Natural killer (NK) cells are lymphocytes well suited for adoptive immunotherapy. Attempts with adoptive NK cell immunotherapy against ovarian cancer have proven unsuccessful, with the main limitations including failure to expand and diminished effector function. We investigated if incubation of NK cells with interleukin (IL)-12, IL-15, and IL-18 for 16h could produce cytokine-induced memory-like (CIML) NK cells capable of enhanced function against ovarian cancer. NK cells were preactivated briefly with IL-12, IL-15, and IL-18, rested, then placed against ovarian cancer targets to assess phenotype and function via flow cytometry. Real-time NK-cell-mediated tumor-killing was evaluated. Using ascites cells and cell-free ascites fluid, NK cell proliferation and function within the immunosuppressive microenvironment was evaluated in vitro. Finally, CIML NK cells were injected intraperitoneal (IP) into an in vivo xenogeneic mouse model of ovarian cancer. CIML NK cells demonstrate enhanced cytokine (IFN-γ) production and NK-cell-mediated killing of ovarian cancer. NK cells treated overnight with cytokines led to robust activation characterized by temporal shedding of CD16, induction of CD25, and enhanced proliferation. CIML NK cells proliferate more with enhanced effector function compared to controls in an immunosuppressive microenvironment. Finally, human CIML NK cells exhibited potent antitumor effects within a xenogeneic mouse model of ovarian cancer. CIML NK cells have enhanced functionality and persistence against ovarian cancer in vitro and in vivo, even when exposed to ascites fluid. These findings provide a strategy for NK cell-based immunotherapy to circumvent the immunosuppressive nature of ovarian cancer.
Identifiants
pubmed: 30658847
pii: S0090-8258(19)30039-3
doi: 10.1016/j.ygyno.2019.01.006
pmc: PMC6430659
mid: NIHMS1518836
pii:
doi:
Substances chimiques
IL15 protein, human
0
IL18 protein, human
0
Interleukin-15
0
Interleukin-18
0
Interleukins
0
Recombinant Proteins
0
Tumor Necrosis Factor-alpha
0
Interleukin-12
187348-17-0
Interferon-gamma
82115-62-6
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
149-157Subventions
Organisme : NCI NIH HHS
ID : P30 CA077598
Pays : United States
Organisme : NCI NIH HHS
ID : P01 CA065493
Pays : United States
Organisme : NCI NIH HHS
ID : R21 CA150085
Pays : United States
Organisme : NCI NIH HHS
ID : R35 CA197292
Pays : United States
Organisme : NCI NIH HHS
ID : P01 CA111412
Pays : United States
Organisme : NCI NIH HHS
ID : P50 CA136393
Pays : United States
Informations de copyright
Copyright © 2019. Published by Elsevier Inc.
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