Cytokine-induced memory-like natural killer cells have enhanced function, proliferation, and in vivo expansion against ovarian cancer cells

Abstract

Objective: 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 16 hours could produce cytokine-induced memory-like (CIML) NK cells capable of enhanced function against ovarian cancer. Methods: 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 NKcell-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. Results: CIML NK cells demonstrate enhanced cytokine (IFN-γ) production and NK-cellmediated killing of ovarian cancer. NK cells treated overnight with cytokines led to robust *

Phenotypic and functional characterization of natural killer cells in rheumatoid arthritis-regulation with interleukin-15

“…Cytokine-induced memory-like (CIML) NK cells refers to NK cells,when pre-activated with IL-12, IL-15, and IL-18, may exhibit enhanced function when re-activated following a resting period cultured with low dose IL-15 9 . CIML NK cells have enhanced anti-leukemic and anti-tumor capacity over conventional NK cells 10,11 . However, the role of CIML NK cells in autoimmunity remains to be determined.…”

Human cytokine-induced memory-like NK cells preserve increased glycolysis but the glycolytic-dependence of their effector functions differ between stimuli

“…IL-12/15/18-preactivated NK cells have emerged as a powerful tool to treat leukemia 11 , and their potential is also being explored in therapies against other malignancies [13][14][15]17 .…”

“…Further studies revealed similar behavior of human IL-12/15/18stimulated NK cells, showing an enhanced cytokine production following restimulation 11,13,[20][21][22][23][24] , and increased proliferation 11,13,20 . After IL-12/15/18-stimulation, the phenotype of NK cells includes changes in the expression of activating and inhibitory receptors, and chemokine and cytokine receptors 11,13,20,22,[25][26][27] . Interestingly, it has been also demonstrated that cytokine-stimulation modifies the metabolic activity of NK cells 28,29 , although this aspect has been poorly explored in human IL-12/15/18-stimulated NK cells.…”

“…Previous studies have shown that NK cells can modify the expression of nutrient transporters following cytokine-stimulation 30,[37][38][39][40][41][42][43] . 13,20,22,25,26 . This feature allows CIML NK cells to proliferate in response to low doses of IL-2, as we and others have previously…”

“…These cells have been proven to be useful in mouse and rat models of several malignancies, including acute myeloid leukemia, T-cell acute lymphoblastic leukemia, multiple myeloma, lymphoma, melanoma, ovarian cancer and hepatocellular carcinoma [11][12][13][14][15][16][17] . Regarding to humans, CIML NK cells have shown their safety and efficacy in the treatment of acute myeloid leukemia patients 11 , and are currently being tested in several clinical trials (NCT01898793, NCT02782546, NCT03068819, NCT04024761, NCT04290546 and NCT04354025, from clinicaltrials.gov).…”