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

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 Registration: ClinicalTrials.gov, identifier NCT03760536.

Exercise-induced modulation of monocytes in breast cancer survivors.

BACKGROUND: Exercise training reduces inflammation in breast cancer survivors; however, the mechanism is not fully understood. OBJECTIVES: The effects of acute and chronic exercise on monocyte toll-like receptor (TLR2 and 4) expression and intracellular cytokine production were examined in sedentary breast cancer survivors. METHODS: Eleven women with stage I, II, or III breast cancer within one year of treatment completion performed an acute, intermittent aerobic exercise trial. Blood samples were obtained before, immediately, and 1 h after a 45-min acute exercise trial that was performed before and after 16 weeks of combined aerobic and resistance. LPS-stimulated intracellular IL-1ß, TNF, and IL-6 production, and TLR2 and TLR4 expression were evaluated in CD14+CD16- and CD14+CD16+ monocytes using flow cytometry. RESULTS: Exercise training decreased IL-1ß+CD14+CD16- proportion (24.6%, p=0.016), IL-1ß+CD14+CD16- mean fluorescence intensity (MFI) (-9989, p=0.014), IL-1ß+CD14+CD16+ MFI (-11101, p=0.02), and IL-6+CD14+CD16- proportion (16.9%, P=0.04). TLR2 and TLR4 expression did not change following exercise training but decreased 1 h after acute exercise in CD14+CD16- (-63, p=0.002) and CD14+CD16+ (-18, p=0.006) monocytes, respectively. Immediately after the acute exercise, both monocyte subgroup cell concentration increased, with CD14+CD16+ concentrations being decreased at 1 h post without changes in intracellular cytokine production. CONCLUSIONS: Exercise training reduced monocyte intracellular pro-inflammatory cytokine production, especially IL-1ß, although these markers did not change acutely. While acute exercise downregulated the expression of TLR2 and TLR4 on monocytes, this was not sustained over the course of training. These results suggest that the anti-inflammatory effect of combined aerobic and resistance exercise training in breast cancer survivors may be, in part, due to reducing resting monocyte pro-inflammatory cytokine production.

Exercise training partially rescues impaired mucosal associated invariant t-cell mobilization in breast cancer survivors compared to healthy older women.

Exercise may attenuate immunosenescence with aging that appears to be accelerated following breast cancer treatment, although limited data on specific cell types exists and acute and chronic exercise have been investigated independently in older adults. PURPOSE: To determine the mucosal associated invariant T (MAIT) cell response to acute exercise before (PRE) and after (POST) 16 weeks of exercise training in breast cancer survivors (BCS) and healthy older women (CON). METHODS: Age-matched BCS and CON performed 45 min of intermittent cycling at 60% peak power output wattage. Blood samples were obtained at rest, immediately (0 h) and 1 h after exercise to determine MAIT cell counts, frequency, and intracellular cytokine expression. RESULTS: At PRE, MAIT cell counts were greater in CON (137%) than BCS at 0 h (46%, p < 0.001), with increased MAIT cell frequency in CON but not BCS. TNFα+ and IFNγ+ MAIT cell counts increased at 0 h by ~120% in CON (p < 0.001), while BCS counts and frequencies were unchanged. Similar deficits were observed in CD3+ and CD3+ CD8+ cells. At POST, exercise-induced mobilization and egress of MAIT cell counts and frequency showed trends towards improvement in BCS that approached levels in CON. Independent of group, TNFα frequency trended to improve (p = 0.053). CONCLUSIONS: MAIT mobilization in older BCS following acute exercise was attenuated; however, exercise training may partially rescue these initial deficits, including greater sensitivity to mitogenic stimulation. Using acute exercise before and after interventions provides a unique approach to identify age- and cancer-related immuno-dysfunction that is less apparent at rest.