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Background The increasing role of exercise training in cancer care is built on evidence that exercise can reduce side effects of treatment, improve physical functioning and quality of life. We and others have shown in mouse tumor models, that exercise leads to an adrenalin-mediated increased influx of T and NK cells into the tumor, altering the tumor microenvironment (TME) and leading to reduced tumor growth. These data suggest that exercise could improve immune responses against cancer cells by increase immune cell infiltration to the tumor and potentially having an impact on disease progression. Additionally, there are data to suggest that infiltration of T and NK cells into the TME is correlates with response to immune checkpoint inhibitors in patients. We have therefore initiated the clinical trial HI AIM, to investigate if high intensity exercise can mobilize and increase infiltration of immune cells in the TME in patients with lung cancer. Methods HI AIM (NCT04263467) is a randomized controlled trial (70 patients, 1:1) for patients with non-small cell lung cancer. Patients in the treatment arm, receive an exercise-intervention consisting of supervised and group-based exercise training, comprising primarily intermediate to high intensity interval training three times per week over 6 weeks. All patients will also receive standard oncological treatments; checkpoint inhibitors, checkpoint inhibitors combined with chemotherapy or oncological surveillance. Blood samples and biopsies (ultrasound guided), harvested before, during and after the 6-week training program, will form basis for immunological measurements of an array of immune cells and markers. Primary outcome is circulating NK cells. Secondary outcome is other circulating immune cells, infiltration of immune cells in tumor, inflammatory markers, aerobic capacity measured by VO 2 max test, physical activity levels and quality of life measured by questionnaires, and clinical outcomes. Discussion To our knowledge, HI AIM is the first project to combine supervised and monitored exercise in patients with lung cancer, with rigorous analyses of immune and cancer cell markers over the course of the trial. Data from the trial can potentially support exercise as a tool to mobilize cells of the immune system, which in turn could potentiate the effect of immunotherapy. Trial registration The study was prospectively registered at ClinicalTrials.gov on February 10 th 2020, ID: NCT04263467. https://clinicaltrials.gov/ct2/show/NCT04263467

Natural killer (NK) cells are a population of innate immune cells known to play a pivotal role against tumor spread. In multiple murine models, it was shown that physical exercise had the potential to increase NK cell antitumor activity through their mobilization and tissue redistribution in an interleukin (IL)‐6 and epinephrine‐dependent manner. The translation of this finding to patients is unclear. In this randomized pilot trial, we analyzed blood samples of patients with resectable breast or colon cancer who were randomized into an evidence‐based moderate‐high intensity resistance and aerobic exercise intervention (n = 8) or a control group (n = 6) during the first 9–12 weeks of (neo)adjuvant chemotherapy. In this pilot, we did not solely focus on statistical significance, but also explored whether average between‐group differences reached 10%. NK cell degranulation was preserved in the exercise group whereas it decreased in the control group resulting in a between‐group difference of 11.4% CD107a+ degranulated NK cells (95%CI = 0.57;22.3, p = 0.04) in the presence and 13.8% (95%CI = −2.5;30.0, p = 0.09) in the absence of an anti‐epidermal growth factor receptor monoclonal antibody (EGFR‐mAb). In line, the between‐group difference of tumor cell lysis was 7.4% (95%CI = −9.1;23.9, p = 0.34), and 13.7% (95%CI = −10.1;37.5, p = 0.23) in favor of the exercise group in the presence or absence of EGFR mAb, respectively. Current explorative analyses showed that exercise during (neo)adjuvant chemotherapy may benefit NK cell activity. Future studies with a larger sample size are needed to confirm this finding and to establish its clinical potential. Trial registration: Dutch trial register number NTR4105. We analyzed blood samples of patients with resectable breast or colon cancer who were randomized into an evidence‐based exercise intervention (n = 8) or control group (n = 6) during the first 9–12 weeks of (neo)adjuvant chemotherapy. NK cell degranulation was preserved during exercise and, although not statistically significant, cytotoxicity levels were 7%–14% higher compared to controls suggesting that physical exercise during (neo)adjuvant chemotherapy might benefit NK cell activity.

Background Type 2 diabetes (T2D) is a chronic metabolic disorder associated with an elevated risk of neurodegenerative diseases (NDs), notably Alzheimer’s disease (AD). The insulin-like growth factor 1 receptor (IGF1R) plays a key role in both T2D and ND pathogenesis by regulating neuroinflammation and neuronal survival. However, the precise molecular mechanisms linking T2D to NDs remain unclear. Objectives This study investigates how IGF1R-mediated immunomodulatory pathways could be leveraged for therapeutic purposes in T2D-related neurodegeneration. It further explores the combined effects of Traditional Chinese Medicine (TCM) and structured exercise on IGF1R signaling and their potential to mitigate T2D-induced neurodegenerative changes. Methods Bioinformatics analyses and in vitro experiments were conducted using SH-SY5Y neuronal cells and primary mouse cortical neurons exposed to amyloid-beta (Aβ) toxicity. IGF1R was overexpressed, and cells were treated with CS at varying concentrations. Cell viability, apoptosis, inflammatory cytokines, oxidative stress markers, and macrophage polarization were assessed using CCK-8, flow cytometry, ELISA, fluorescence microscopy, and related methods. Results Elevated IGF1R expression reduced Aβ-induced neuronal death and inflammation. CS administration increased IL-10 levels, suppressing pro-inflammatory cytokines (IL-1β, TNF-α), and promoted M2-like macrophage polarization, enhancing neurotrophic factors, such as brain-derived neurotrophic factor (BDNF) and anti-inflammatory responses. Conclusions IGF1R is pivotal in regulating neuroinflammation and neuronal apoptosis in T2D-associated neurodegeneration. Combined TCM and structured exercise may beneficially modulate IGF1R-dependent signaling and protect neurons. Further clinical studies are needed to validate these findings and assess their therapeutic potential. Graphical Abstract

The remarkable success of cancer immunotherapies has provided new hope to cancer patients. Unfortunately, a significant proportion of patients remain unable to respond to immunotherapy or maintain durable clinical responses. The lack of objective responses likely results from profound immune dysfunction often observed in patients with cancer. There is substantial evidence that exercise and physical activity can reduce incidence and improve outcomes in cancer patients. As the immune system is highly responsive to exercise, one potential avenue to improve immune function is through exercise and physical activity. A single event of dynamic exercise results in the substantial mobilization of leukocytes with increased functional capacities into the circulation. Chronic, or long-term, exercise leads to higher physical fitness in terms of greater cardiorespiratory function and/or muscle strength and endurance. High aerobic capacity, as measured by maximal oxygen uptake, has been associated with the reduction of dysfunctional T cells and improvements in the abundance of some T cell populations. To be sure, however, the mechanisms of exercise-mediated immune changes are both extensive and diverse. Here, we examine the evidence and theorize how acute and chronic exercise could be used to improve responses to cancer immunotherapies including immune checkpoint inhibitors, dendritic cell vaccines, natural killer cell therapies, and adoptive T cell therapies such as chimeric antigen receptor (CAR) T cells. Although the parameters of optimal exercise to yield defined outcomes remain to be determined, the available current data provide a compelling justification for additional human studies and clinical trials investigating the adjuvant use of exercise in immuno-oncology.

Physical activity induces rapid and selective leukocyte mobilization. Among the most responsive cell types to high-intensity exercise are CD8 T cells, key effectors of immune defense against infected cells and cancer. However, comprehensive profiling of acute high-intensity interval training (HIIT)-induced modulation of the CD8 T cell compartment remains lacking. We assessed the effects of a supervised, group-based HIIT session on the CD8+ T cell compartment in 23 healthy participants. Blood was collected at baseline, immediately post-exercise (ex02), and one hour post-exercise (ex60). CD8 T cells were analyzed for virus peptide reactivity using DNA-barcoded peptide-MHC multimer staining targeting 250 peptides. Differentiation status, chemokine receptor expression, and ligand regulation were assessed by flow cytometry and Olink proteomics, and finally, associations between individual characteristics and CD8 T cell mobilization were analyzed. A single HIIT bout induced robust CD8 T cell mobilization followed by substantial egress, which were consistent across fitness levels, body composition and age. Circulating virus-reactive T cells significantly increased in peripheral blood in response to exercise across virus types, including EBV-, SARS-CoV-2- and CMV-specific T cells. HIIT modulated chemokine receptor profiles, and memory subsets were reorganized, reducing terminally differentiated and CD57 , PD-1 , and CD28 cells at ex60 post-exercise. Notably, catecholamines NE and EPI peaked post-exercise, and NE was selectively associated with CD8 T cell mobilization. In conclusion, acute HIIT mobilizes functional, virus-reactive CD8 T cells with features indicative of enhanced migratory and activation potential, supporting translational use from tumor immunology to infectious disease. The study is registered at clinicaltrials.gov (NCT05826496).

TCR-gamma delta (γδ) T-cells are considered important players in the graft-vs.-tumor effect following allogeneic hematopoietic cell transplantation (alloHCT) and have emerged as candidates for adoptive transfer immunotherapy in the treatment of both solid and hematological tumors. Systemic β-adrenergic receptor (β-AR) activation has been shown to mobilize TCR-γδ T-cells to the blood, potentially serving as an adjuvant for alloHCT and TCR-γδ T-cell therapy. We investigated if systemic β-AR activation, using acute dynamic exercise as an experimental model, can increase the mobilization, expansion, and anti-tumor activity of TCR-γδ T-cells isolated from the blood of healthy humans. We also sought to investigate the β-AR subtypes involved, by administering a preferential β -AR antagonist (bisoprolol) and a non-preferential β + β -AR antagonist (nadolol) prior to exercise as part of a randomized placebo controlled cross-over experiment. We found that exercise mobilized TCR-γδ cells to blood and augmented their expansion by ~182% compared to resting blood when stimulated with IL-2 and ZOL for 14-days. Exercise also increased the proportion of CD56+, NKG2D+/CD62L-, CD158a/b/e+ and NKG2A- cells among the expanded TCR-γδ cells, and increased their cytotoxic activity against several tumor target cells (K562, U266, 221.AEH) by 40-60%. Blocking NKG2D on TCR-γδ cells eliminated the augmented cytotoxic effects of exercise against U266 target cells. Furthermore, administering a β + β -AR (nadolol), but not a β -AR (bisoprolol) antagonist prior to exercise abrogated the exercise-induced enhancement in TCR-γδ T-cell mobilization and expansion. Furthermore, nadolol completely abrogated while bisoprolol partially inhibited the exercise-induced increase in the cytotoxic activity of the expanded TCR-γδ T-cells. We conclude that acute systemic β-AR activation in healthy donors markedly augments the mobilization, expansion, and anti-tumor activity of TCR-γδ T-cells and that some of these effects are due to β -AR signaling and phenotypic shifts that promote a dominant activating signal via NKG2D. These findings highlight β-ARs as potential targets to favorably alter the composition of allogeneic peripheral blood stem cell grafts and improve the potency of TCR-γδ T-cell immune cell therapeutics.

This study investigated selected inflammatory responses to acute and chronic exercise in individuals with inflammatory bowel disease (IBD). A systematic review and meta-analysis was conducted on all relevant exercise-based intervention publications with IBD participants. The study included articles that utilised a broad range of acute and chronic exercise interventions, with inflammatory biomarkers measured and symptoms documented, both pre- and post-exercise for those with IBD. The search was limited to studies published in English, the use of human participants, and primary studies, with no restrictions on date of publication or participant's age. Articles were retrieved through the electronic databases: PubMed, SPORTDiscus, and Scopus. This study adhered to Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. Six inflammatory markers were included in the meta-analysis which consisted of five studies. Exercise interventions resulted in no significant difference in IL-6 (SMD = -0.09; 95% CI = -0.49, 0.30; P = 0.64), TNF-α (SMD = 0.08; 95% CI = -0.31, 0.48; P = 0.68), CRP (SMD = -0.04; 95% CI = -0.58, 0.50; P = 0.89), IL-17 (SMD = 0.15; 95% CI = -0.45, 0.76; P = 0.62), leukocytes (SMD = 0.40; 95% CI = -0.53, 1.33; P = 0.40) or lymphocytes (SMD = 0.32; 95% CI = -0.33, 0.97; P = 0.33), thus, indicating exercise may have no effect on inflammatory markers in IBD. Bowel symptoms improved following regular moderate exercise that incorporated stress management. Heterogeneity among the identified literature may have led to exercise interventions being ineffective in reducing inflammation. Although the limited number of eligible studies may reduce the reliability of results, it emphasises the need for additional research in this domain. Importantly, no adverse symptomatic responses to exercise indicate that exercise is safe for IBD patients.

Physical exercise represents an effective preventive and therapeutic strategy beneficially modifying the course of multiple diseases. The protective mechanisms of exercise are manifold; primarily, they are elicited by alterations in metabolic and inflammatory pathways. Exercise intensity and duration strongly influence the provoked response. This narrative review aims to provide comprehensive up-to-date insights into the beneficial effects of physical exercise by illustrating the impact of moderate and vigorous exercise on innate and adaptive immunity. Specifically, we describe qualitative and quantitative changes in different leukocyte subsets while distinguishing between acute and chronic exercise effects. Further, we elaborate on how exercise modifies the progression of atherosclerosis, the leading cause of death worldwide, representing a prime example of a disease triggered by metabolic and inflammatory pathways. Here, we describe how exercise counteracts causal contributors and thereby improves outcomes. In addition, we identify gaps that still need to be addressed in the future.

This article focuses on how nutrition may help prevent and/or assist with recovery from the harmful effects of strenuous acute exercise and physical training (decreased immunity, organ injury, inflammation, oxidative stress, and fatigue), with a focus on nutritional supplements. First, the effects of ketogenic diets on metabolism and inflammation are considered. Second, the effects of various supplements on immune function are discussed, including antioxidant defense modulators (vitamin C, sulforaphane, taheebo), and inflammation reducers (colostrum and hyperimmunized milk). Third, how 3-hydroxy-3-methyl butyrate monohydrate (HMB) may offset muscle damage is reviewed. Fourth and finally, the relationship between exercise, nutrition and COVID-19 infection is briefly mentioned. While additional verification of the safety and efficacy of these supplements is still necessary, current evidence suggests that these supplements have potential applications for health promotion and disease prevention among athletes and more diverse populations.

Growing evidence supports the importance of lifestyle and environmental exposures—collectively referred to as the ‘exposome’—for ensuring immune health. In this narrative review, we summarize and discuss the effects of the different exposome components (physical activity, body weight management, diet, sun exposure, stress, sleep and circadian rhythms, pollution, smoking, and gut microbiome) on immune function and inflammation, particularly in the context of the current coronavirus disease 2019 (COVID-19) pandemic. We highlight the potential role of ‘exposome improvements’ in the prevention—or amelioration, once established—of this disease as well as their effect on the response to vaccination. In light of the existing evidence, the promotion of a healthy exposome should be a cornerstone in the prevention and management of the COVID-19 pandemic and other eventual pandemics.