The Effects of 16 Weeks of Exercise Training on Neutrophil Functions in Breast Cancer Survivors

Abstract

Following therapy, breast cancer survivors (BCS) have an increased risk of infections because of age and cancer dysregulation of inflammation and neutrophil functions. Neutrophil functions may be improved by exercise training, although limited data exist on exercise and neutrophil functions in BCS.Sixteen BCS [mean age: 56 (SD 11) years old] completed 16 weeks of community-based exercise training and a 45-minute acute bout of cycling before (Base) and after (Final) the exercise training program. Exercise training consisted of 3 x 40 – 60 minute mixed mode aerobic exercises, comprising 10 – 30 minutes aerobic and 30 minutes resistance training. At Base and Final, we took BCS blood samples before (PRE), immediately after (POST), and 1 hour after (1Hr) acute exercise to determine neutrophil counts, phenotype, bacterial killing, IL-6, and IL-8 levels. Eleven healthy, age- and physical activity levels-matched women (Control) completed the acute bout of exercise once as a healthy response reference. Resting Responses. BCS and Controls had similar Base PRE absolute neutrophil counts [mean (SD): 3.3 (1.9) v 3.1 (1.2) x 109/L, p=0.801], but BCS had lower bacterial phagocytosis [3991 (1233) v 4881 (417) MFI, p=0.035] and higher oxidative killing [6254 (1434) v 4709 (1220) MFI, p=0.005], lower CD16 [4159 (1785) v 7018 (1240) MFI, p<0.001], lower CXCR2 [4878 (1796) v 6330 (1299) MFI, p=0.032] and higher TLR2 [98 (32) v 72 (17) MFI, p=0.022] expression, while IL-6 [7.4 (5.4) v 4.0 (2.7) pg/mL, p=0.079] levels were marginally higher and IL-8 [6.0 (4.7) v 7.9 (5.0) pg/mL, p=0.316] levels similar. After 16 weeks of training, compared to Controls, BCS Final PRE phagocytosis [4510 (738) v 4881 (417) MFI, p=0.146] and TLR2 expression [114 (92) v 72 (17) MFI, p=0.148] were no longer different. Acute Exercise Responses. As compared to Controls, at Base, BCS phagocytic Pre-Post response was lower [mean difference, % (SD): 12% (26%), p=0.042], CD16 Pre-Post response was lower [12% (21%), p=0.016] while CD16 Pre-1Hr response was higher [13% (25%), p=0.022], TLR2 Pre-Post response was higher [15% (4%) p=0.002], while IL-8 Pre-Post response was higher [99% (48%), p=0.049]. As compared to Controls, following 16 weeks of training BCS phagocytic Pre-Post response [5% (5%), p=0.418], CD16 Pre-1Hr response [7% (7%), p=0.294], TLR2 Pre-Post response [6% (4%), p=0.092], and IL-8 Pre-Post response [1% (9%), p=0.087] were no longer different. Following cancer therapy, BCS may have impaired neutrophil functions in response to an acute bout of exercise that are partially restored by 16 weeks of exercise training. The improved phagocytosis of bacteria in BCS may represent an exercise-induced intrinsic improvement in neutrophil functions consistent with a reduced risk of infectious disease.Clinical Trial RegistrationClinicalTrials.gov, identifier NCT03760536.

Integrating molecular biomarkers in breast cancer rehabilitation. What is the current evidence? A systematic review of randomized controlled trials

“…On the other hand, several reports emphasized the positive effects of physical exercise and rehabilitation in increasing anti-inflammatory cytokines concentrations and promoting the release of anti-inflammatory regulatory T-cells ( Pierce et al, 2009 ; Mancuso, 2016 ). This hypothesis has been supported by preclinical and clinical studies highlighting the key role of physical exercise in the regulation of chemokine expression, promoting cytotoxic immune cell activity and downregulating suppressor immune cells ( Upadhyay et al, 2018 ; Liu et al, 2020 ; Bartlett et al, 2021 ). Accordingly, it is widely accepted that chronic inflammation biomarkers (i.e., interleukin 6 (IL-6), tumor necrosis factor-α (TNF-α), macrophage migration inhibitory factor (MIF), and C-reactive protein (CRP)) might have a role in the oncogenesis process, promoting their oncogenic effects in both genetic and epigenetic alterations ( Trinchieri, 2012 ; Zitvogel et al, 2017 ; Barabutis et al, 2018 ).…”

Behavioral factors to modulate immunotherapy efficacy in cancer

“…For example, immune markers of NK cells differed: exercise had an inhibitory effect on the absolute number of NK cells in patients with breast cancer (106), an augmenting effect on NK cells percentages in patients with lung cancer (107), whereas no effect in another cohort of patients with breast cancer and other solid tumors was observed (17,22). Comparably, IL-6 expression differed after exercise interventions, showing either a decrease in some studies (24-26), but no effects (17,20,23,108), or an increase in other studies (16,18,109). Given the diverse effects that exercise has on the number of immune cells in patients with cancer, for instance in NK cells, it has been suggested that exercise may instead affect the cytotoxic activity of the immune cells, mirroring the effects exercise has on healthy individuals through inflammatory response pathways (110,111).…”

“…There is both pre-clinical and clinical evidence for a relation between exercise and the immune system and effectiveness of exercise during chemotherapy or radiotherapy (16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26). In patients, exercise has been associated with reduced side effects of cancer and its treatment (27, 28).…”

“…Thereby, exercise improved the physical and mental health and the overall self-reported quality of life of patients (27-29). Patient-reported outcome measures were complemented by immunological readouts, including the number of NK cells, expression of IL-6, or TNFa production (16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26). In observational and randomized controlled exercise trials -both increases and decreases in defined immune markers were reported.…”

“…Behavior, and consequently behavioral interventions, have been shown to broadly affect the immune system (15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26), and as such may help to improve therapeutic efficacy. Previous studies have shown that behavioral therapies improved quality of life and energy levels in patients receiving chemotherapy, radiotherapy or hormonal therapy (27)(28)(29)(30)(31)(32)(33).…”