Endurance training slows breast tumor growth in mice by suppressing Treg cells recruitment to tumors

Abstract

Background Aerobic exercise has been shown to slow tumor progression in rodents and humans, but the mechanisms behind this effect are still unclear. Here we show that aerobic exercise in the form of chronic endurance training suppresses tumor recruitment of FoxP3 + Treg cells thus enhancing antitumor immune efficiency. Methods Adult wild-type and athymic BALB/c female mice were endurance-trained for 8 weeks. Circulating leukocytes as well as muscle and liver mtDNA copy number were compared to aged-matched concurrent sedentary controls to establish systemic effects. 4 T1 murine mammary tumor cells were injected subcutaneously to the 4th mammary pad at the end of the training period. Tumor growth and survival rates were compared, together with antitumor immune response. Results Exercised wild-type had 17% slower growth rate, 24% longer survival, and 2-fold tumor-CD + 8/FoxP3 + ratio than sedentary controls. Exercised athymic BALB/c females showed no difference in tumor growth or survival rates when compared to sedentary controls. Conclusions Cytotoxic T cells are a significant factor in endurance exercise-induced suppression of tumor growth. Endurance exercise enhances antitumor immune efficacy by increasing intratumoral CD8 + /FoxP3 + ratio. Electronic supplementary material The online version of this article (10.1186/s12885-019-5745-7) contains supplementary material, which is available to authorized users.

Run for your life – an integrated virtual tissue platform for incorporating exercise oncology into immunotherapy

“…The comparison yielded a classification of distinct aerobic fitness levels, each of which yields a distinct tumor growth curve (Figure 4). A similar effect was shown qualitatively in pre-clinical studies [21,22]. [23] have discovered a distribution of tumor growth rates in the population (measured in tumor doubling times), which was shown to be lognormal.…”

“…This second hypothesis, the one we focused on here, connects exercise-induced increased hypoxia-tolerance to more efficient anti-tumor immune response, and requires chronic endurance training (CET) which can be achieved in pre-clinical exercise oncology with forced running wheels [21,28]. The idea here is that CET induces hypoxia tolerance in the skeletal muscles and in other tissues, and as a result TMEs are more susceptible to the degradation of HIF1α [31].…”

“…The idea here is that CET induces hypoxia tolerance in the skeletal muscles and in other tissues, and as a result TMEs are more susceptible to the degradation of HIF1α [31]. This degradation is an upstream factor in a signaling cascade leading to increased anti-tumor immune efficiency, as HIF1α is known to recruit, via myokine signaling [10,11,32], Trges into the tumor micro-environment, which suppress CTLs [9,21]. Support for this potential mechanism in humans that connects CET with reduced intratumoral Treg density comes from a small pilot study in which recently diagnosed breast cancer patients were subject to a short exercise session before treatment, and their excised tumor presented with fewer intratumoral Tregs [24].…”

“…Time series of TME sections in early stage progression of a solid tumor. To probe the intricate dynamics of anti-tumor immune response in the early stages of a solid tumor progression, the model can yield an observation window into the TME in different stages of growth (7A-D), and can be used to test competing hypotheses on tumor immune cells population dynamics by comparing these snapshots to real life immunohistochemistry (7E, [21]), where cross sections from exercised ("FIT") and sedentary ("SED") mice show different intratumoral CD8 + /FOXP3 + ratios.…”

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.…”