Physical Activity Plus Energy Restriction Prevents 4T1.2 Mammary Tumor Progression, MDSC Accumulation, and an Immunosuppressive Tumor Microenvironment.

Abstract

Physical activity and the prevention of weight gain decrease breast cancer incidence and improve survival. Unraveling the biological mechanisms underlying these cancer prevention effects is difficult because activity and dietary restriction are often linked. The goal of this study was to determine whether physical activity (PA), preventing weight gain via energy restriction (ER), or the combination was most effective in delaying tumor growth, reducing metastatic progression, and improving survival in the 4T1.2 mammary tumor model. Furthermore, we determined whether any of these interventions prevented the expansion of protumor immunosuppressive cells and altered the tumor microenvironment (TME). Female BALB/c mice (n = 7-20/group) were randomized to sedentary (SED) or PA wheel cages and fed ad libitum (AL) or 90% of control food intake (ER). After 8 weeks on the interventions, mice were inoculated with 5 × 104 4T1.2luc cells into the 4th mammary fat pad and continued on their respective intervention. PA+ER significantly delayed primary tumor growth (final tumor volume, 0.193 ± 0.042 vs. 0.369 ± 0.049 cm3, P < 0.001), reduced metastatic burden in the lungs (0.72 ± 0.36 vs. 16.27 ± 6.98, P = 0.054) and increased survival (median survival, 68 vs 40 days, P = 0.043) compared with SED+AL mice. PA+ER also reduced the expression level of metastatic and immunosuppressive genes and resulted in favorable changes in immune cell infiltrates in the tumor. These data suggest that both PA and ER are needed to reduce tumor growth, delay metastatic progression, and improve survival, and that this protection is associated with changes in immune-mediated mechanisms.