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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.

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.

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PURPOSE:Acute bouts of dynamic exercise elicit a profound mobilization of effector lymphocytes into the blood compartment, resulting in cellular redistribution and increased immunosurveillance of peripheral tissues. This effect, in conjunction with the release of catecholamines and myokines, is now known to play a mechanistic role in the anti-cancer effects of regular exercise against many solid malignancies. However, little data exists in this arena concerning hematological malignancies such as lymphoma. We tested the hypothesis that exercising mice would demonstrate reduced tumor progression relative to sedentary mice in a subcutaneous murine lymphoma model. METHODS: 8-12 week old male and female Balb/C mice were injected subcutaneously in the right flank with 1 x 10 6 A20 lymphoma cells and assigned to either sedentary (n = 32) or exercise (n = 31) conditions. Mice assigned to exercise received a running wheel one day post A20 cell injections. Body weight and tumor progression (calipers) were assessed every 3-4 days until the end of the experiment on day 40. RESULTS: Both sedentary and exercising mice gained a significant amount of weight due to tumor growth (p < 0.0001) over 40 days. However, upon resection of the tumor after sacrifice, there was no difference in tumor-free body weight between sedentary and exercising mice (25.09 ± 5.63 vs. 24.67 ± 4.86 g, respectively; p = 0.7886). On average, mice with access to a running wheel ran ~5.2 km/day; this voluntary wheel running translated to a significantly slowed tumor progression over the course of the experiment relative to sedentary mice (170.52 ± 163.18 vs. 239.75 ± 182.21 mm 2 on day 40, p = 0.0042). CONCLUSION: Regular physical activity is now known to be inversely related with the risk of acquiring many different forms of cancer, as well as disease progression after diagnosis. These data suggest that regular exercise in mice reduces the progression of lymphoma, adding a hematological malignancy to the list of solid cancers (e.g. breast, skin) that now have in vivo evidence of slowed progression with exercise training. Future work will determine the immune cells involved in exerting the anti-cancer effects of regular exercise against lymphoma and other hematologic malignancies.