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Immune-mediated tumor microenvironment remodeling depends on the high fat diet duration
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Edité par CCSD -
International audience. Breast cancer ranks among the most prevalent cancers globally, particularly affecting women (1). Contributing risk factors include non-optimal lifestyle combining dietary imbalance and a sedentary, obesity, and postmenopausal status, all linked to a long-term hormonal and inflammation exposure (2). Physical activity confers protection against breast cancer by influencing hormone levels, immune responses, and oxidative defences (3,4). This study aimed to evaluate the impact of prolonged obesity on the efficacy of physical activity in preventing and managing breast cancer during mammary tumorigenesis.Ovariectomized 35-week-old C57BL/6 mice were subjected to an enriched environment to induce spontaneous physical activity and were fed a high-fat diet (HFD) throughout the experiment. After 42 days (Short-term (ST), n=10) or 88 days (Long-term, LT, n=10) on the HFD, syngenic EO771 cells were implanted into the 4th mammary glands, and tumor growth was monitored for 30 days. Upon sacrifice, the tumor microenvironment (TME) immune infiltrate and metabolic parameters were assessed using various methods. Data, expressed as mean ± SEM, were analyzed using a Mann-Whitney test.The median survival was significantly shorter in the LT group compared to the ST group (22 days vs 25.5 days, p=0.0296). Despite similar spontaneous physical activity and individual food intake in both groups, the LT group exhibited higher visceral adipose tissue mass (p=0.04) and reduced skeletal muscle mass (p=0.0765). In the TME, the LT group showed decreased proportions of NK cells (p=0.05) and TCD8+ cells (p=0.002), with a tendency for increased T regulatory cells (p=0.1), resulting in a collapse of the T8/Treg ratio (p=0.03). Additionally, the LT group displayed a significant decrease in tumor triglyceride content (p=0.0143) accompanied by altered enzyme activities indicative of oxidative stress.In our experimental conditions, prolonged exposure to a high-fat diet (LT HFD) was associated with tumor growth despite an elevated spontaneous physical activity. LT HFD promoted a tolerogenic TME by enhancing lipid consumption and oxidative stress while recruiting anti-tumor immune cells. Future investigations should explore the inter-organ exchanges between tumor and tissues such as adipose tissue and skeletal muscles. The prospect of combining enforced physical activity with immunotherapy may counteract the long-term effects of a hypercaloric diet.
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