Acute Exercise Increases NK Cell Mitochondrial Respiration and Cytotoxicity against Triple-Negative Breast Cancer Cells under Hypoxic Conditions

Abstract

Purpose Triple-negative breast cancer (TNBC) is an aggressive, highly metastatic malignancy with high recurrence rates. Hypoxia is a hallmark of the TNBC tumor micro-environment, which promotes tumor growth while impairing NK cell cytotoxic functions. Although acute exercise improves NK cell function under normoxic conditions, the impact of exercise on NK cell cytotoxic functions under hypoxic conditions mimicking O2 tensions observed in solid tumors is unknown. Methods The cytotoxic functions of resting and post-exercise NK cells isolated from thirteen young inactive healthy women were assessed against breast cancer cells expressing different levels of hormone receptors (MCF-7 and MDA-MB-231) under normoxic and hypoxic conditions. Mitochondrial respiration and H2O2 production rates of the TNBC-activated NK cells were assessed via high-resolution respirometry. Results Under hypoxia, post-exercise NK cells exhibited greater killing of TNBC than resting NK cells. Further, post-exercise NK cells were more likely to kill TNBC under hypoxia than normoxic conditions. In addition, mitochondrial respiration associated with oxidative (OXPHOS) capacity of TNBC-activated NK cells was greater in post-exercise cells than resting cells under normoxia, but not under hypoxia. Finally, acute exercise was associated with reduced mitochondrial H2O2 production by NK cells in both conditions. Conclusions Together, we present crucial interrelationships between hypoxia and exercise-induced changes in NK cell functions against TNBC cells. By modulating their mitochondrial bioenergetic functions, we postulate that acute exercise improves NK cell function under hypoxic conditions. Specifically, NK cell O2 and H2O2 flow (pmols·s-1·million NK cells-1) changes in response to 30 min cycling suggest that exercise primes NK cell tumor killing by reducing mitochondrial oxidative stress, and thus rescuing their function when exposed to harsh hypoxic environments as observed in the microenvironment of breast solid tumors.