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Can exercise increase natural killer cell infiltration of the prostate?

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BJU International
Authors:
Daniel A. Galvão
Daniel A. Galvão
Daniel A. Galvão
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Dennis Taaffe at Edith Cowan University
Dennis Taaffe
Jin-Soo Kim at Edith Cowan University
Jin-Soo Kim
Robert Usher Newton at Edith Cowan University
Robert Usher Newton
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Can exercise increase natural killer cell infiltration of
the prostate?
Regular exercise is a well-established intervention to reduce
prostate cancer treatment toxicities [1]. In addition, higher
levels of physical activity are associated with longer prostate
cancer survival [2]. However, the mechanisms underlying the
protective effect of exercise against tumour development/
progression remain to be clearly elucidated. In this context,
Djurhuus et al. [3] have reported on the first human study
examining the effects of an exercise intervention on natural
killer (NK) cell infiltration in localised prostate cancer. This is
an important question: NK cells are constantly on high alert
for malignant cell transformation, monitoring target cells for
surface expression of NK cell-activating receptors, and are
Exercise-
Induced IL-6
Exercise-
Induced IL-6
Exercise-induced
Catecholamines
NK cells
Mobilisation ↑
NK cells
Infiltration ↑
NK cells Infiltration ↑; Tumour size ↓ in animal model
Men with
Localised
Prostate
Cancer
Within EX group Between Group
EX group
CON
group
Pre-
exercise
Post-exercise
NK Cells in
Healthy
Prostate
Tissue ↑
NK Cells in
Tumour ↑
High-Intensity
Interval Training
Per-protocol analyses
ITT analyses:
No changes in
tumour NK cells
Fig. 1 NK cell infiltration following exercise. CON, control; EX, exercise; IL-6, interleukin 6.
Ó2022 BJU International.
Published by John Wiley & Sons Ltd. www.bjui.org wileyonlinelibrary.com
BJU Int 2023; 131: 1–3 doi:10.1111/bju.15904
Editorial
... The other RCT used a preoperative aerobic high intensity interval training four-times per week from time of inclusion until scheduled surgery. It was reported that there was a withingroup increase in tumour NK cells in the exercise group, and a between-group difference in healthy prostatic tissue, though NK cell frequency was low (45,64). Nevertheless, the study did not show a difference in the number of infiltrating NK cells in the tumours from baseline to follow-up between groups, neither with the intention-to-treat nor the per-protocol analysis. ...
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Exercise training to increase tumour natural killer‐cell infiltration in men with localised prostate cancer: a randomised controlled trial
Article
Full-text available
Objectives To explore the effects of preoperative high‐intensity interval training (HIIT) compared to usual care on tumour natural killer (NK)‐cell infiltration in men with localised prostate cancer (PCa), as NK‐cell infiltration has been proposed as one of the key mechanisms whereby exercise can modulate human tumours. Patients and Methods A total of 30 patients with localised PCa undergoing radical prostatectomy (RP) were randomised (2:1) to either preoperative aerobic HIIT four‐times weekly (EX; n = 20) or usual care (CON; n = 10) from time of inclusion until scheduled surgery. Tumour NK‐cell infiltration was assessed by immunohistochemistry (CD56⁺) in diagnostic core needle biopsies and corresponding prostatic tissue from the RP. Changes in cardiorespiratory fitness, body composition, blood biochemistry, and health‐related quality of life were also evaluated. Results The change in tumour NK‐cell infiltration did not differ between the EX and CON groups (between‐group difference: −0.09 cells/mm², 95% confidence interval [CI] –1.85 to 1.66; P = 0.913) in the intention‐to‐treat analysis. The total number of exercise sessions varied considerably from four to 30 sessions. The per‐protocol analysis showed a significant increase in tumour NK‐cell infiltration of 1.60 cells/mm² (95% CI 0.59 to 2.62; P = 0.004) in the EX group. Further, the total number of training sessions was positively correlated with the change in NK‐cell infiltration (r = 0.526, P = 0.021), peak oxygen uptake (r = 0.514, P = 0.035) and peak power output (r = 0.506, P = 0.038). Conclusion Preoperative HIIT did not result in between‐group differences in tumour NK‐cell infiltration. Per‐protocol and exploratory analyses demonstrate an enhanced NK‐cell infiltration in PCa. Future studies are needed to test the capability of exercise to increase tumour immune cell infiltration.
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Exercise Training and Natural Killer Cells in Cancer Survivors: Current Evidence and Research Gaps Based on a Systematic Review and Meta-analysis
Article
Full-text available
  • Mar 2022
Background Exercise training can positively impact the immune system and particularly natural killer (NK) cells, at least in healthy people. This effect would be of relevance in the context of cancer given the prominent role of these cells in antitumor immunity. In this systematic review and meta-analysis, we aimed to summarize current evidence on the effects of exercise training on the levels and function of NK cells in cancer survivors (i.e., from the time of diagnosis until the end of life). Methods Relevant articles were searched in PubMed, Scopus, Web of Science and Cochrane Central Register of Controlled Trials (until January 11, 2022). Randomized controlled trials (RCT) of exercise training (i.e., non-acute) interventions vs usual care conducted in cancer survivors and assessing NK number and/or cytotoxic activity (NKCA) before and upon completion of the intervention were included. Methodological quality of the studies was assessed with the PEDro scale, and results were meta-analyzed using a random effects (Dersimoian and Laird) model. Results Thirteen RCT including 459 participants (mean age ranging 11–63 years) met the inclusion criteria. Methodological quality of the studies was overall fair (median PEDro score = 5 out of 10). There was heterogeneity across studies regarding cancer types (breast cancer, non-small cell lung cancer and other solid tumors), treatment (e.g . , receiving vs having received chemotherapy), exercise modes (aerobic or resistance exercise, Tai Chi, Yoga) and duration (2–24 weeks). No consistent effects were observed for NK number in blood (mean difference [MD]: 1.47, 95% confidence interval [CI] − 0.35 to 3.29, p = 0.113) or NKCA as assessed in vitro (MD: − 0.02, 95%CI − 0.17 to 0.14, p = 0.834). However, mixed results existed across studies, and some could not be meta-analyzed due to lack of information or methodological heterogeneity. Conclusions Current evidence does not support a significant effect of exercise training intervention on NK cells in blood or on their ‘static response’ (as assessed in vitro) in cancer survivors. Several methodological issues and research gaps are highlighted in this review, which should be considered in future studies to draw definite conclusions on this topic.
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Physical Activity and Survival After Prostate Cancer Diagnosis in the Health Professionals Follow-Up Study
Article
Full-text available
  • Feb 2011
  • J CLIN ONCOL
To determine whether higher physical activity after prostate cancer (PCa) diagnosis decreases risk of overall and PCa-specific death. We evaluated physical activity in relation to overall and PCa mortality among 2,705 men in the Health Professionals Follow-Up Study diagnosed with nonmetastatic PCa observed from 1990 to 2008. Proportional hazards models were used to evaluate physical activity and time to overall and PCa-specific death. Among men who lived at least 4 years after their postdiagnosis physical activity assessment, we documented 548 deaths, 20% of which were a result of PCa. In multivariable analysis, men who were physically active had lower risk of all-cause mortality (P(trend) < .001) and PCa mortality (P(trend) = .04). Both nonvigorous activity and vigorous activity were associated with significantly lower overall mortality. Those who walked ≥ 90 minutes per week at a normal to very brisk pace had a 46% lower risk of all-cause mortality (hazard ratio [HR] 0.54; 95% CI, 0.41 to 0.71) compared with shorter durations at an easy walking pace. Men with ≥ 3 hours per week of vigorous activity had a 49% lower risk of all-cause mortality (HR, 0.51; 95% CI, 0.36 to 0.72). For PCa-specific mortality, brisk walking at longer durations was suggestively inverse but not statistically significant. Men with ≥ 3 hours per week of vigorous activity had a 61% lower risk of PCa death (HR, 0.39, 95% CI, 0.18 to 0.84; P = .03) compared with men with less than 1 hour per week of vigorous activity. Men exercising vigorously before and after diagnosis had the lowest risk. In men with PCa, physical activity was associated with lower overall mortality and PCa mortality. A modest amount of vigorous activity such as biking, tennis, jogging, or swimming for ≥ 3 hours a week may substantially improve PCa-specific survival.
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Exercise-induced myokines and their effect on prostate cancer
Article
  • Jun 2021
Exercise is recognized by clinicians in the field of clinical oncology for its potential role in reducing the risk of certain cancers and in reducing the risk of disease recurrence and progression; yet, the underlying mechanisms behind this reduction in risk are not fully understood. Studies applying post-exercise blood serum directly to various types of cancer cell lines provide insight that exercise might have a role in inhibiting cancer growth via altered soluble and cell-free blood contents. Myokines, which are cytokines produced by muscle and secreted into the bloodstream, might offer multiple benefits to cellular metabolism (such as a reduction in insulin resistance, improved glucose uptake and reduced adiposity), and blood myokine levels can be altered with exercise. Alterations in the levels of myokines such as IL-6, IL-15, IL-10, irisin, secreted protein acidic risk in cysteine (SPARC), myostatin, oncostatin M and decorin might exert a direct inhibitory effect on cancer growth via inhibiting proliferation, promoting apoptosis, inducing cell-cycle arrest and inhibiting the epithermal transition to mesenchymal cells. The association of insulin resistance, hyperinsulinaemia and hyperlipidaemia with obesity can create a tumour-favourable environment; exercise-induced myokines can manipulate this environment by regulating adipose tissue and adipocytes. Exercise-induced myokines also have a critical role in increasing cytotoxicity and the infiltration of immune cells into the tumour.
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Exercise training effects on natural killer cells: a preliminary proteomics and systems biology approach
Article
  • Jan 2021
  • EXERC IMMUNOL REV
Background: Regular exercise, particularly moderate-intensity continuous training (MICT), can improve immune function. Natural killer (NK) cells, a subset of lymphocytes that react to infections, are the most responsive innate immune cells to exercise, but the mechanisms underlying this are poorly understood. A type of exercise training that is gaining popularity in recent years is high-intensity interval training (HIIT), but how it affects NK cells is largely unknown. In fact, intense exercise has been traditionally viewed as a potential stressor to immune homeostasis. The purpose of this study was to determine in healthy, previously untrained adults (N=8 [3 male; 40±6 years]) the effects of an intervention consisting of 4-week MICT followed by 4-week HIIT on NK cells as compared with a pre-training (baseline) state. Methods: Participants were studied at three time points: baseline, mid-intervention (after MICT), and post-intervention (after HIIT). Main assessments included cytotoxicity assays, flow-cytometry analysis of NK cell surface markers, and interrogation of the cellular proteome using a systems biology approach. Results: A significant time effect was found for NK cell cytotoxicity (p<0.001), which was increased ~10-fold at both midand post-intervention versus baseline. No significant intervention effect was found for NK surface receptor expression, except for CXCR3 determined as mean fluorescence intensity (p=0.044, although with no significant differences in post hoc pairwise comparisons). The proteins showing a higher differential expression (Log2 fold-change > 10 and false discovery rate [FDR] q-value < 0.001) were COP9 signalosome subunit 3 (COPS3), DnaJ heat shock protein family member B11 (DNAJB11), histidyl-TRNA synthetase 1 (HARS), NIMA related kinase 9 (NEK9), nucleoporin 88 (NUP88), phosphoinositide-3-kinase regulatory subunit 1 (PIK3R1), regulator of chromosome condensation 2 (RCC2), TAO kinase 3 (TAOK3), transducin beta like 2 (TBL2), and ring finger protein 40 (RNF40). All were upregulated at mid-intervention compared with baseline, with the exception of HARS, which was downregulated. Four enriched pathways (FDR p<25%) were found: two related to transmembrane transport and cellular composition (downregulated at mid-intervention vs baseline), and two related to oxidation- reduction reactions (regulated at post-intervention versus baseline). Conclusion: A progressive exercise intervention of MICT followed by HIIT induces a remarkable improvement in NK function compared with the untrained state, although at the mechanistic level the pathways involved seem to differ over time during the intervention.
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Control of Metastasis by NK Cells
Article
  • Aug 2017
  • CANCER CELL
The metastatic spread of malignant cells to distant anatomical locations is a prominent cause of cancer-related death. Metastasis is governed by cancer-cell-intrinsic mechanisms that enable neoplastic cells to invade the local microenvironment, reach the circulation, and colonize distant sites, including the so-called epithelial-to-mesenchymal transition. Moreover, metastasis is regulated by microenvironmental and systemic processes, such as immunosurveillance. Here, we outline the cancer-cell-intrinsic and -extrinsic factors that regulate metastasis, discuss the key role of natural killer (NK) cells in the control of metastatic dissemination, and present potential therapeutic approaches to prevent or target metastatic disease by harnessing NK cells.
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Voluntary Running Suppresses Tumor Growth through Epinephrine- and IL-6-Dependent NK Cell Mobilization and Redistribution
Article
  • Mar 2016
  • CELL METAB
Regular exercise reduces the risk of cancer and disease recurrence. Yet the mechanisms behind this protection remain to be elucidated. In this study, tumor-bearing mice randomized to voluntary wheel running showed over 60% reduction in tumor incidence and growth across five different tumor models. Microarray analysis revealed training-induced upregulation of pathways associated with immune function. NK cell infiltration was significantly increased in tumors from running mice, whereas depletion of NK cells enhanced tumor growth and blunted the beneficial effects of exercise. Mechanistic analyses showed that NK cells were mobilized by epinephrine, and blockade of b-adrenergic signaling blunted training-dependent tumor inhibition. Moreover, epinephrine induced a selective mobilization of IL-6- sensitive NK cells, and IL-6-blocking antibodies blunted training-induced tumor suppression, intratumoral NK cell infiltration, and NK cell activation. Together, these results link exercise, epinephrine, and IL-6 to NK cell mobilization and redistribution, and ultimately to control of tumor growth.
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Combined Resistance and Aerobic Exercise Program Reverses Muscle Loss in Men Undergoing Androgen Suppression Therapy for Prostate Cancer Without Bone Metastases: A Randomized Controlled Trial
Article
  • Nov 2009
  • J CLIN ONCOL
Androgen suppression therapy (AST) results in musculoskeletal toxicity that reduces physical function and quality of life. This study examined the impact of a combined resistance and aerobic exercise program as a countermeasure to these AST-related toxicities. Between 2007 and 2008, 57 patients with prostate cancer undergoing AST (commenced > 2 months prior) were randomly assigned to a program of resistance and aerobic exercise (n = 29) or usual care (n = 28) for 12 weeks. Primary end points were whole body and regional lean mass. Secondary end points were muscle strength and function, cardiorespiratory capacity, blood biomarkers, and quality of life. Analysis of covariance was used to compare outcomes for groups at 12 weeks adjusted for baseline values and potential confounders. Patients undergoing exercise showed an increase in lean mass compared with usual care (total body, P = .047; upper limb, P < .001; lower limb, P = .019) and similarly better muscle strength (P < .01), 6-meter walk time (P = .024), and 6-meter backward walk time (P = .039). Exercise also improved several aspects of quality of life including general health (P = .022) and reduced fatigue (P = .021) and decreased levels of C-reactive protein (P = .008). There were no adverse events during the testing or exercise intervention program. A relatively brief exposure to exercise significantly improved muscle mass, strength, physical function, and balance in hypogonadal men compared with normal care. The exercise regimen was well tolerated and could be recommended for patients undergoing AST as an effective countermeasure to these common treatment-related adverse effects.
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