The influence of physical activity in the anti-tumor immune response in experimental breast tumor

Abstract

This study aimed to investigate the influence of physical activity in innate immunity to conduce to an effective antitumoral immune response analyzing the phenotype and activation status of infiltrating cells. We analysed the intracellular cytokines and the transcription factors of tumor infiltrating lymphocytes (TILS) and spleen leukocytes. The Nos2 gene expression was evaluated in spleen cells and futhermore the ROS production was measured and spleen cells; another cell evaluated was dendritic cells (TIDCs), their cytokines expression and membrane molecules; finally to understood the results obtained, we analysed the dendritic cells obtained from bone marrow. Were used female Balb/c mice divided into 4 groups: two controls without tumor, sedentary (GI) and trained (GII) and two groups with tumor, sedentary (GIII) or trained (GIV). The physical activity (PA) was realized acoording swimming protocol. Tumor was induced by injection of 4T1 cells. All experiments were performed in biological triplicate. After the experimental period, the tumor was removed and the cells were identified by flow cytometry with labeling to CD4, CD8, CD11c, CD11b, CD80, CD86 and Ia, and intracelular staining IL-10, IL-12, TNF-α, IFN-γ, IL-17, Tbet, GATA3, RORγt and FoxP3. The bone marrow of the animals was obtained to analyse the derivated DCs by flow cytometry and culture cells to obtain the supernatant to measure the cytokines. Our results demonstrated that the PA inhibit the tumoral growth although not to change the number of TILS, but reduced expression of GATA-3, ROR-γT, related with poor prognosis, and TNF-α intracellular; however occur one significantly reduction in TIDCS, but these cells expressed more co-stimulatory and presentation molecules. Furthermore, we observed that the induced PA stimulated the gene expression of Tbet and the production of inflammatory cytokines suggesting an increase of Th1 systemic response. The results evaluating the systemic influence in DCs showed that the PA improve significantly the number of those cells in bone marrow as well the number of co-stimulatory molecules. Therefore, we could conclude that PA influence the innate immunity by interfering to promote in process of maturation of DCs both in tumor and systemically, that by its turn promote a modification in acquired immune cells, representing by T helper to induce an important alteration transcription factors that are responsible to maintain a suppressive microenviroment, and thereby, allowing the latter cells can thus activate antitumor immune response. The PA was able improve the Th1 systemic response by enhance to Tbet gene expression, promote a slightly increased of Th1-type cytokines and decrease Gata3 and Foxp3 gene expression in which can inhibit the Th1 immune response.

Moderate Exercise Modulates Tumor Metabolism of Triple-Negative Breast Cancer

“…Interruption of training after inoculation of tumor cells favored tumor growth similarly to the full-time sedentary group. Corroborating our results, Bianco and colleagues [24] showed that forced swimming exercise reduced tumor volume in animals inoculated with 2 × 10 5 4T1 cells. In addition, voluntary physical exercise has been shown to reduce tumor growth rate after mice were inoculated with 5 × 10 4 [22] or 1 × 10 4 [23] 4T1 cells.…”

“…Investigations of the effects of physical exercise on experimental TNBC are still scarce and wield heterogeneous results [22][23][24][25][26]. Here we showed that moderate aerobic physical training, both 8 weeks before and 4 weeks after the inoculation of 4T1 cancer cells, reduces tumor growth.…”

Physical Activity and Breast Cancer Prevention: Possible Role of Immune Mediators

“…Nineteen studies investigated the effect of PA interventions on cancer immune outcomes using preclinical breast cancer models ( Table 1 ). Transplantable tumor models were used in 14 studies ( 31 , 32 , 34 , 35 , 44 – 50 , 53 – 55 ), among which six used the 4T1 (or its subclone 4T1.2) TNBC murine mammary tumor model ( 32 , 34 , 35 , 44 , 48 , 54 ). Carcinogen-induced ( n = 3) ( 33 , 56 , 57 ) and genetically-engineered/spontaneous ( n = 2) ( 51 , 52 ) mammary tumor models were also used.…”

Exercício físico aeróbico de intensidade moderada reduz a velocidade de crescimento e modula o metabolismo energético tumoral em modelo experimental de câncer de mama triplo-negativo

“…Adicionalmente, em modelo experimental de melanoma, demonstrou-se que o exercício foi capaz de realçar o conteúdo de células NK, com consequente redução do tamanho tumoral (Pedersen et al, 2016). Entretanto, nenhuma alteração no infiltrado de linfócitos foi observada após exercício físico em meio aquático com modelo experimental de câncer de mama (Bianco et al, 2017). Além disso, estima-se que o exercício aeróbico pode melhorar a perfusão e amenizar a hipoxia tumoral via estímulos angiogênicos e redução na expressão de HIF's em modelos xenográficos de câncer de mama (Betof et al, 2015;Khori et al, 2015;Isanejad et al, 2016;Wiggins et al, 2018).…”

“…semanas-3 e 4), cinco dias por semana durante quatro semanas, teve impacto positivo na redução do volume tumoral em animais inoculados com cinco vezes menos células (i.e. 2x10 5 células 4T1) (Bianco et al, 2017). É importante destacar que em nosso estudo, com exercícios forçados em esteira, tanto o protocolo de treinamento, como a inoculação de células tumorais (i.e.…”