Exercise Induced Immune Modulation - Consequences For Tumor Progression

Maintaining a physically active lifestyle after a cancer diagnosis is associated with a reduced risk of recurrence and mortality. How exercise exerts its beneficial effects is currently unknown. Using pre-clinical models of breast cancer, we have showed that the immune system, and especially CD8+ T-cells, are instrumental for the anti-neoplastic effects of exercise. PURPOSE: The overarching aim was to explore how exercise enhances immune function, through altering the metabolic landscape, and thereby promotes anti-tumoral immune surveillance. METHODS: Twenty moderately active healthy men and women between the age of 18-35 year performed a 3x30 sec all-out sprint exercise. Blood samples were collected before, 3 min after and 1 hour after exercise. CD8+ T-cells were analysed for gene expression, functional markers, metabolism, and cytotoxicity. Functional consequences of exposing CD8+ T-cells to exercise induced metabolites was investigated using mass spectrometry, expression analysis and real time metabolic flux monitoring. RESULTS: The high intensity exercise induced a substantial change in blood metabolites such as lactate, and led to a significant increase in circulating T-cells (CD3+). The number of circulating CD8+ T-cells increased three-fold after exercise compared to baseline. Subpopulation analyses showed that exercise primarily recruited effector cells, with an enhanced IFNγ response to viral antigen and ex vivo tumor cell cytotoxicity. Furthermore, ex vivo experiments showed that lactate can be taken up by activated CD8+ T cells and displace glucose as a primary source of carbon. Activation in the presence of lactate significantly alters the CD8+ T cell transcriptome, including the expression of key effector differentiation markers such as granzyme B and IFNγ. CONCLUSION: The obtained results suggest that the CD8+ fraction of the immune cell populations recruited during exercise have a more pronounced effector function - which can be mediated by exercise induced metabolites and is in line with an enhanced anti-tumoral activity. The Swedish Research Council for Sport Science, P2023-0163. The Swedish Society of Medicine, SLS-871441