EXERCISE-MOBILIZED NK CELLS IMPROVE THE EFFICACY OF CYTOKINE-INDUCED MEMORY-LIKE NK CELLS

Abstract

Natural Killer (NK) cells are a promising immunotherapy to treat leukemia relapse due to their innate cytotoxicity and low treatment-related toxicity. However, persistence and sustained cytotoxicity in vivo remain a challenge. Overnight activation with interleukin (IL) 12, IL-15, and IL-18 generates cytokine-induced memory-like NK (CIML NK) cells. These cells show enhanced cytotoxicity and improved persistence in vivo. Ongoing clinical trials have shown promise with CIML NK cells with high-risk leukemia patients, however, prolonged anti-tumor activity still remains an issue. Acute bouts of exercise have demonstrated a five-fold increase of NK cells in peripheral circulation with highly enriched gene-sets to promote cytotoxicity. Here we investigated whether exercise mobilized NK cells (NKx) enhance production and function of CIML NK cells (CIML NKx). Four healthy donors performed a 20 minute bout of graded exercise on a cycle ergometer with blood samples taken at rest and during the last two-minutes of exercise. NK cells were then isolated from rest (NK) and exercise (NKx) time points, which were each stimulated with the IL-12, IL-15, and IL-18 combination overnight to produce resting CIML NK cells and CIML NKx cells. These were then injected into leukemic-bearing xenogeneic mice to assess in vivo persistence and graft vs leukemia (GvL) effects. Therapeutic treatment with CIML NKx cells exhibited enhanced engraftment, delayed and reduced tumor burden (via bioluminescence imaging (BLI)), increased tumor-free survival and improved overall survival when compared to treatment with CIML NK. These findings suggest improved function and survival with therapeutic use of cytokine stimulated NK cells generated from exercise.