Acute exercise induces distinct quantitative and phenotypical T cell profiles in men with prostate cancer

BackgroundReduced testosterone levels can influence immune system function, particularly T cells. Exercise during cancer reduces treatment-related side effects and provide a stimulus to mobilize and redistribute immune cells. However, it is unclear how conventional and unconventional T cells (UTC) respond to acute exercise in prostate cancer survivors compared to healthy controls.MethodsAge-matched prostate cancer survivors on androgen deprivation therapy (ADT) and those without ADT (PCa) along with non-cancer controls (CON) completed ∼45 min of intermittent cycling with 3 min at 60% of peak power interspersed by 1.5 min of rest. Fresh, unstimulated immune cell populations and intracellular perforin were assessed before (baseline), immediately following (0 h), 2 h, and 24 h post-exercise.ResultsAt 0 h, conventional T cell counts increased by 45%–64% with no differences between groups. T cell frequency decreased by −3.5% for CD3+ and −4.5% for CD4+ cells relative to base at 0 h with CD8+ cells experiencing a delayed decrease of −4.5% at 2 h with no group differences. Compared to CON, the frequency of CD8+CD57+ cells was −18.1% lower in ADT. Despite a potential decrease in maturity, ADT increased CD8+perforin+ GMFI. CD3+Vα7.2+CD161+ counts, but not frequencies, increased by 69% post-exercise while CD3+CD56+ cell counts increased by 127% and were preferentially mobilized (+1.7%) immediately following the acute cycling bout. There were no UTC group differences. Cell counts and frequencies returned to baseline by 24 h.ConclusionFollowing acute exercise, prostate cancer survivors demonstrate normal T cell and UTC responses that were comparable to CON. Independent of exercise, ADT is associated with lower CD8+ cell maturity (CD57) and perforin frequency that suggests a less mature phenotype. However, higher perforin GMFI may attenuate these changes, with the functional implications of this yet to be determined

Cytomegalovirus Infection Impairs the Mobilization of Tissue-Resident Innate Lymphoid Cells into the Peripheral Blood Compartment in Response to Acute Exercise

Circulating immune cell numbers and phenotypes are impacted by high-intensity acute bouts of exercise and infection history with the latent herpesviruses cytomegalovirus (CMV). In particular, CMV infection history impairs the exercise-induced mobilization of cytotoxic innate lymphoid cells 1 (ILC1) cells, also known as NK cells, in the blood. However, it remains unknown whether exercise and CMV infection modulate the mobilization of traditionally tissue-resident non-cytotoxic ILCs into the peripheral blood compartment. To address this question, 22 healthy individuals with or without CMV (20–35 years—45% CMVpos) completed 30 min of cycling at 70% VO2 max, and detailed phenotypic analysis of circulating ILCs was performed at rest and immediately post-exercise. We show for the first time that a bout of high-intensity exercise is associated with an influx of ILCs that are traditionally regarded as tissue-resident. In addition, this is the first study to highlight that latent CMV infection blunts the exercise-response of total ILCs and progenitor ILCs (ILCPs). These promising data suggest that acute exercise facilitates the circulation of certain ILC subsets, further advocating for the improvements in health seen with exercise by enhancing cellular mobilization and immunosurveillance, while also highlighting the indirect deleterious effects of CMV infection in healthy adults

Angiogenesis and fibrosis in a volumetric skeletal muscle loss injury using mesenchymal stem cells in a PEGylated fibrin gel on an extracellular matrix

Volumetric Muscle Loss (VML) injury can result from trauma and in military personnel with wound in combat. VML lead to the loss of substantial mass of muscle mass, inherent regenerative capacity, thus can fail to retain functional muscle. Previous work in our lab, has shown partial functional and morphological repair from the injection of PEGylated fibrin gel combined with mesenchymal stem cells (MSC) to skeletal muscle-derived decellularied extracellular matrix (ECM) following fifty-six days after VML injury model. To further investigate the vascularization, innervation, and fibrosis in this model, trichrome, and immunohistochemical analyses were performed in three groups: saline (SAL), mesenchymal stem cell (MSC), and MSCs in PEGylated fibrin gel (PEG+MSC). The PEG+MSC group had as significantly lower percentage of fibrosis than the SAL group in the top, middle and bottom regions within ECM, as well as lower fibrosis only in the middle region when compared to the MSC group (p <0.05). The MSC group had lower fibrosis only in the middle region than SAL group (p <0.05). Similarly, PEG+MSC has higher percentage of cellular area than SAL group in all regions, and the MSC group had as higher percentage of cellular area when compared to SAL group only in the middle region (p <0.05). The only difference in cellular material shown was between the PEG+MSC group and the MSC group in the middle region of ECM (p <0.05). Following a fifty-six day recovery, the blood vessel density of PEG+MSC, and MSC groups were higher than the SAL group (p <0.05) in middle region, with no difference in other regions. The blood vessel ratio of PEG+MSC, and MSC groups were significantly higher than the SAL group (p <0.05) in all regions.  Kinesiology and Health Educatio

The Effects of Exercise on Innate Lymphoid Cell Metabolism and Function in Cancer

Immunosenescence refers to the gradual decrease in immune competency over time, which is strongly associated with increased risk of cancer and a rise in morbidity and mortality among the elderly. Regular physical activity can be beneficial to the immune system by potentially decreasing the frequency of senescent immune cells and reducing mortality risk in cancer patients and survivors. However, less is known on the impact of acute exercise on “aggressive” cancers, such as hormone receptor negative breast cancers. Further, the mechanistic underpinnings of the exercise-associated improvements in the immune response to cancer remains unclear. In this context, past studies have suggested that acute bouts of exercise lead to a preferential mobilization of immune cells with potent anti-cancer effects in the peripheral blood compartment. In addition to promoting immune cell mobilization, it is likely that exercise also improves the functionality and metabolism of specific immune cells such as NK cells. As such, this dissertation aimed to investigate the effects of exercise on immune cell function and metabolism in sedentary individuals. The first chapter examined whether acute bouts of exercise and infection history with latent herpesviruses cytomegalovirus (CMV) impact the mobilization of distinct populations of Innate Lymphoid Cells (ILCs). This study, published in Viruses, showed that individual bouts of acute exercise mobilize traditionally tissue resident ILCs into the blood compartment. However, latent CMV infection history reduces the ingress of total ILC (tILC), and progenitor ILC (ILCP). The second chapter investigated the effects of exercise on Natural Killer (NK) cells bioenergetics and cytotoxic functions when NK cells are activated by aggressive breast cancer subtypes under hypoxic environment. This is the first study to show that a single acute bout of exercise recues the NK cell function lost due to hypoxic conditions. Further, activated NK cells by triple-negative breast cancer cells showed increased mitochondrial oxidative capacity and decreased Reactive Oxygen Species (ROS) following exercise, both known to being associated with improved and impaired functions respectively. Overall, this dissertation provides new insights into our understanding of NK cell function in response to exercise, playing a powerful role to enhance immunosurveillance and protect from cancer incidence

Impact of maximal exercise on immune cell mobilization and bioenergetics

Abstract Acute aerobic exercise increases the number and proportions of circulating peripheral blood mononuclear cells (PMBC) and can alter PBMC mitochondrial bioenergetics. In this study, we aimed to examine the impact of a maximal exercise bout on immune cell metabolism in collegiate swimmers. Eleven (7 M/4F) collegiate swimmers completed a maximal exercise test to measure anaerobic power and capacity. Pre‐ and postexercise PBMCs were isolated to measure the immune cell phenotypes and mitochondrial bioenergetics using flow cytometry and high‐resolution respirometry. The maximal exercise bout increased circulating levels of PBMCs, particularly in central memory (KLRG1+/CD57−) and senescent (KLRG1+/CD57+) CD8+ T cells, whether measured as a % of PMBCs or as absolute concentrations (all p < 0.05). At the cellularlevel, the routine oxygen flow (IO2 [pmol·s−1·106 PBMCs−1]) increased following maximal exercise (p = 0.042); however, there were no effects of exercise on the IO2 measured under the LEAK, oxidative phosphorylation (OXPHOS), or electron transfer (ET) capacities. There were exercise‐induced increases in the tissue‐level oxygen flow (IO2‐tissue [pmol·s−1·mL blood−1]) for all respiratory states (all p < 0.01), except for the LEAK state, after accounting for the mobilization of PBMCs. Future subtype‐specific studies are needed to characterize further maximal exercise's true impact on immune cell bioenergetics

Cytomegalovirus Infection Impairs the Mobilization of Tissue-Resident Innate Lymphoid Cells into the Peripheral Blood Compartment in Response to Acute Exercise

Circulating immune cell numbers and phenotypes are impacted by high-intensity acute bouts of exercise and infection history with the latent herpesviruses cytomegalovirus (CMV). In particular, CMV infection history impairs the exercise-induced mobilization of cytotoxic innate lymphoid cells 1 (ILC1) cells, also known as NK cells, in the blood. However, it remains unknown whether exercise and CMV infection modulate the mobilization of traditionally tissue-resident non-cytotoxic ILCs into the peripheral blood compartment. To address this question, 22 healthy individuals with or without CMV (20–35 years—45% CMVpos) completed 30 min of cycling at 70% VO2 max, and detailed phenotypic analysis of circulating ILCs was performed at rest and immediately post-exercise. We show for the first time that a bout of high-intensity exercise is associated with an influx of ILCs that are traditionally regarded as tissue-resident. In addition, this is the first study to highlight that latent CMV infection blunts the exercise-response of total ILCs and progenitor ILCs (ILCPs). These promising data suggest that acute exercise facilitates the circulation of certain ILC subsets, further advocating for the improvements in health seen with exercise by enhancing cellular mobilization and immunosurveillance, while also highlighting the indirect deleterious effects of CMV infection in healthy adults

Breast cancer growth and proliferation is suppressed by the mitochondrial targeted furazano[3,4-b]pyrazine BAM15

Abstract Background Enhanced metabolic plasticity and diversification of energy production is a hallmark of highly proliferative breast cancers. This contributes to poor pharmacotherapy efficacy, recurrence, and metastases. We have previously identified a mitochondrial-targeted furazano[3,4-b]pyrazine named BAM15 that selectively reduces bioenergetic coupling efficiency and is orally available. Here, we evaluated the antineoplastic properties of uncoupling oxidative phosphorylation from ATP production in breast cancer using BAM15. Methods The anticancer effects of BAM15 were evaluated in human triple-negative MDA-MB-231 and murine luminal B, ERα-negative EO771 cells as well as in an orthotopic allograft model of highly proliferative mammary cancer in mice fed a standard or high fat diet (HFD). Untargeted transcriptomic profiling of MDA-MB-231 cells was conducted after 16-h exposure to BAM15. Additionally, oxidative phosphorylation and electron transfer capacity was determined in permeabilized cells and excised tumor homogenates after treatment with BAM15. Results BAM15 increased proton leak and over time, diminished cell proliferation, migration, and ATP production in both MDA-MB-231 and EO771 cells. Additionally, BAM15 decreased mitochondrial membrane potential, while inducing apoptosis and reactive oxygen species accumulation in MDA-MB-231 and EO771 cells. Untargeted transcriptomic profiling of MDA-MB-231 cells further revealed inhibition of signatures associated with cell survival and energy production by BAM15. In lean mice, BAM15 lowered body weight independent of food intake and slowed tumor progression compared to vehicle-treated controls. In HFD mice, BAM15 reduced tumor growth relative to vehicle and calorie-restricted weight-matched controls mediated in part by impaired cell proliferation, mitochondrial respiratory function, and ATP production. LC-MS/MS profiling of plasma and tissues from BAM15-treated animals revealed distribution of BAM15 in adipose, liver, and tumor tissue with low abundance in skeletal muscle. Conclusions Collectively, these data indicate that mitochondrial uncoupling may be an effective strategy to limit proliferation of aggressive forms of breast cancer. More broadly, these findings highlight the metabolic vulnerabilities of highly proliferative breast cancers which may be leveraged in overcoming poor responsiveness to existing therapies

Natural killer cell mobilization and egress following acute exercise in men with prostate cancer

NEW FINDINGS: What is the central question of this study? What are the characteristics of the NK cell response following acute moderate-intensity aerobic exercise in prostate cancer survivors and is there a relationship between stress hormones and NK cell mobilization? What is the main finding and its importance? NK cell numbers and proportions changed similarly between prostate cancer survivors and controls following acute exercise. Consecutive training sessions can likely be used without adverse effects on the immune system during prostate cancer treatment. ABSTRACT: Prostate cancer treatment affects multiple physiological systems, although the immune response during exercise has been minimally investigated. The objective was to characterize the natural killer (NK) cell response following acute exercise in prostate cancer survivors. Prostate cancer survivors on androgen deprivation therapy (ADT) and those without (PCa) along with non-cancer controls (CON) completed a moderate intensity cycling bout. NK cells were phenotyped before and 0, 2 and 24 h after acute exercise using flow cytometry. CD56 total NK cell frequency increased by 6.2% at 0 h (P < 0.001) and decreased by 2.5% at 2 h (P < 0.01) with similar findings in CD56dim cells. NK cell counts also exhibited a biphasic response. Independent of exercise, ADT had intracellular interferon γ (IFNγ) expression that was nearly twofold higher than CON (P < 0.01). PCa perforin expression was reduced by 11.4% (P < 0.05), suggesting these cells may be more prone to degranulation. CD57- NK cells demonstrated increased perforin and IFNγ frequencies after exercise with no change within the CD57+ populations. All NK and leukocyte populations returned to baseline by 24 h. NK cell mobilization and egress with acute exercise appear normal, as cell counts and frequencies in prostate cancer survivors change similarly to CON. However, lower perforin proportions (PCa) and higher IFNγ expression (ADT) may alter NK cytotoxicity and require further investigation. The return of NK cell proportions to resting levels overnight suggests that consecutive training sessions can be used without adverse effects on the immune system during prostate cancer treatment