The immune system: A common link mediating exercise effects on the tumour microenvironment and skeletal muscle mitochondria?
Buss, Linda Anita
Exercise reduces the risk of developing a range of different cancers and has been associated with improved cancer patient survival. However, preclinical studies suggest that in some cases, exercise may be ineffective or even accelerate tumour growth. Understanding the mechanisms behind the exercise-cancer relationship may help us better identify which individuals are likely to benefit from exercise, and aid the development of new treatment strategies. The overarching aim of this thesis was to investigate the mechanisms behind the effect of exercise on cancer outcomes, including its effects on the tumour microenvironment, tumour growth rate, cancer-associated muscle dysfunction and interaction with immunotherapy. Specifically, I investigated the response of the tumour and skeletal muscle to exercise (alone and in combination with anti-PD-1 immunotherapy) by characterising changes in tumour-infiltrating immune cells, tumour hypoxia and blood flow, and markers of muscle mitochondria in mice with transplanted melanoma or breast cancers. I hypothesised that exercise would enhance anti-tumour immune responses and improve tumour blood flow, thereby boosting the efficacy of concurrent immunotherapy. However, I also hypothesised that tumour burden would impair muscular adaptation to exercise, thereby potentially limiting exercise effects on the tumour. Exercise, both alone and in combination with anti-PD-1 treatment, produced changes in the number and proportion of CD8+ tumour-infiltrating T cells. The direction of these changes varied with treatment and tumour type, but did not significantly affect tumour growth rate. Furthermore, breast cancer inhibited skeletal muscle mitochondrial adaptation to exercise. This impaired response was restored by anti-PD-1 treatment (in mice with either tumour type), suggesting that the immune system plays a critical role in effective muscular adaptation to exercise. Finally, I found that muscular COX-IV expression (as a proxy for mouse ‘fitness’ and an indicator of effective muscle response to exercise), was associated with slower tumour growth and reduced tumour hypoxia in hyperlipidaemic ApoE-/- but not wild-type mice. Taken together, these results highlight the immune system as an important mediator of exercise effects on both the tumour and muscle tissue, and suggest that exercise may ‘normalise’ the negative effects of metabolic abnormalities on tumour progression. Therefore, this work has provided mechanistic understanding of the exercise-cancer relationship and has generated the hypothesis that the combination of exercise and immunotherapy may be a potential novel therapeutic strategy for the prevention of cancer-associated muscle wasting.
Advisor: Dachs, Gabi; Currie, Margaret; Hock, Barry; Ang, Abel; Robinson, Bridget
Degree Name: Doctor of Philosophy
Degree Discipline: Pathology and Biomedical Science
Publisher: University of Otago
Keywords: Cancer; Tumour microenvironment; Cancer immunology; Exercise; Physical activity; Exercise oncology; Mitochondria; Hypoxia; Immune checkpoint inhibitors; Anti-PD-1; Immunotherapy; Exercise response
Research Type: Thesis