Lower peak numbers, blunted diurnal rhythms of immune cell distribution, and sleep disruption in metastatic breast cancer

Rationale : The peak number of protective immune cells measured in the blood at the zenith of their diurnal rhythm is a measure of their overall capacity for immunoprotection. Rhythmic diurnal changes in blood immune cell numbers reflect a redistribution of cells from the blood to other body compartments, and back into the blood. This redistribution may be critical for leukocyte maintenance and for the surveillance and effector functions of the immune system. Methods : We investigated diurnal changes in absolute numbers of NK cells in patients with metastatic breast cancer (MBC) (n=48) and controls (n=19). Sleep quality was measured by home actigraphy. Leukocyte differentials were combined with flow cytometry to calculate NK cell numbers in whole blood samples obtained every 4h, starting 12 h (T1) after the midpoint of sleep on day 1 and ending 12 h (T7) after the midpoint of sleep on day 2. Results : In agreement with the literature, control subjects showed peak blood NK cell numbers at T1, with a decrease to their diurnal trough at around the sleep midpoint (T4), followed by a return to diurnal peak numbers 12 h later. Compared to controls, patients with MBC showed significantly lower peak NK cell numbers (p=0.039), suggesting an overall decrease in NK-cell-mediated immunoprotection for patients. Interestingly, among patients, higher peak NK cell numbers were associated with a longer disease-free interval (p=0.036) and higher Karnofsky Performance Rating (p=0.083, trend), collectively indicating an association between higher peak NK cell numbers and better health and functional status. Compared to controls, patients with MBC also showed a smaller peak to trough decrease (p=0.006) that suggests reduced diurnal NK cell redistribution among different immune compartments which could also decrease immunoprotection. We further investigated the relationship between sleep disruption and damped NK cell rhythms in MBC patients. Higher average wake time after sleep onset was associated with a smaller peak to trough decrease (R= − 0.38, p=0.006). The average number of awakenings was also associated with a smaller peak to trough decrease (R= − 0.36, p=0.014). In contrast, average sleep efficiency was associated with a larger peak to trough decrease (R= − 0.40, p=0.005), indicating a positive association between better sleep and a healthier diurnal NK cell rhythm. Conclusion : These results suggest that patients with MBC have reduced NK-cell-mediated immunoprotection compared to controls and that among patients, higher NK cell numbers are related to longer disease-free interval and better Karnofsky status. Patients with MBC also show decreased diurnal NK cell redistribution compared to controls, and among patients, reduced diurnal NK cell redistribution is associated with increased sleep disruption.