Systemic hypoxia affects exercise-mediated antitumor cytotoxicity of natural killer cells

Natural killer cells (NKs) are important to the clearance of transformed cells. This investigation elucidates how systemic hypoxia influences mobilization of the NK subsets and cytotoxicity of NKs to nasopharyngeal carcinoma cells (NPCs) during exercise. Sixteen sedentary men performed six distinct experimental tests in an air-conditioned normobaric hypoxia chamber: high-intensity exercise [HE; up to maximal O₂ consumption (V̇O_{2 max})] under 21% O₂; moderate-intensity exercise (ME; 50% V̇O_{2 max} for 30 min) under 12%, 15%, and 21% O ₂; and breathing 12% and 15% O₂ for 30 min at rest. The results demonstrated that 21% O₂ HE, but not ME, increased cellular perforin/granzyme B/interferon-γ levels in NKs and interferon-γ concentration in NK-NPC coincubation, and also promoted capacity of NKs to bind to NPCs and NK-induced CD95 expression and phosphatidylserine exposure of NPCs. However, the HE simultaneously increased percentages of the replicative senescent (CD57⁺ and CD28^-) NKs and the NKs with inhibitory receptors (KLRG1⁺) that entered the bloodstream from peripheral tissues. Breathing 12% and 15% O₂ at rest did not influence mobilization of NK subsets and cytotoxicity of NKs to NPCs. Although both 12% and 15% O₂ ME increased NK count, perforin/granzyme B/interferon-γ levels, NK-NPC binding, and NK-induced CD95 expression and apoptosis of NPC, only 12% O₂ ME increased percentages of the NKs with CD57⁺/CD28^-/KLRG1⁺ in blood. Therefore, we conclude that systemic hypoxic exposure affects redistribution of NK subsets and anti-NPC cytotoxicity of NKs during exercise in a concentration-dependent manner. Moreover, exposure to 12% O₂ promotes the NK cytotoxicity with mobilizing the replicative senescent/inhibitory NKs into the bloodstream during ME.