Relative role of physical activity on mitochondrial density and bioenergetics of infiltrating T lymphocytes from tumor microenvironment

Abstract

In the last decades, there has been a remarkable progress in the treatment of different types of cancer, which has improved the prognosis of patients with this disease. Despite this, cancer remains the second leading cause of death in the world and it is also the leading cause of death in developed countries. Therefore, strategies capable of attenuating tumor initiation, progression and aggressiveness are extremely important for reducing incidence and mortality caused by cancer. In this context, recent studies have been demonstrating the importance of maintaining tumor-infiltrating T lymphocyte (TILs-T) function for the attenuation of tumor progression. However, although immunotherapies have been succeeding in current cancer clinic, most patients still do not respond to these therapies, highlighting the importance of better understanding the mechanisms responsible for TILs-T dysfunction. In accordance with this, it has recently been shown that mitochondrial metabolism and morphology are capable of modulating T cell function, although glycolytic metabolism is still the main focus of study of the TILs-T metabolism. In fact, it has been observed that TILs-T exhibit a global metabolic insufficiency, associated with a persistent loss of mitochondrial function and content, which is directly related to an impaired TILs-T effector function, and lower interferon-gamma (INF-³) and TNF-± production. This loss of TILs-T mitochondrial density and function is a tumor microenvironment specificity, and largely independent of PD-1 blockade and of regulatory T cells suppression. In addition, it has also been shown that mitochondrial morphology and dynamics can modulate TILs-T function. Considering this, it is well known that regular physical activity promotes several beneficial adaptations in the body, in which aerobic fitness improvement plays a main role. This improved aerobic fitness in response to exercise is largely due to a significant increase in mitochondrial number and volume, associated to an improvement of mitochondrial function and metabolism. In convergence, regular physical activity has emerged as a possible strategy to attenuate tumor progression. In fact, preliminary data from our group have been demonstrating the therapeutic role of physical activity on tumor progression in B16 melanoma and CT26 colon cancer models in mice. However, the mechanisms underlining the beneficial effects of regular physical exercise on tumor progression are still not clear. Therefore, the aim of the present project is to evaluate whether aerobic physical activity can attenuate or prevent the loss of TILs-T mitochondrial content and function, restoring mitochondrial metabolism and, consequently, the T cell effector function. In order to test this, the project will be conducted in two parts; in the first part, we are going to evaluated the effect of regular aerobic physical activity on mitochondrial bioenergetics, density and morphology of tumor infiltrating and non-infiltrating T cells of different cancer models in mice. In the second part of the project, we intend to explore, through the transcriptome analysis of tumor infiltrating and non-infiltrating T cells, the mechanisms involved in the T cell effector function improvement due to regular physical activity.