Exercise and Lung Cancer

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PROJECT SUMMARY Clinical and epidemiologic studies have demonstrated that exercise reduces the incidence and improves the prognosis of numerous types of cancer; however, the mechanisms by which exercise exerts its anti-cancer effects remain poorly understood. Most exercise studies have been performed in breast cancer; however, as breast cancer is obesity-associated, insulin-driven, and only weakly immunogenic, it is likely that exercise may work differently in cancer types that are strongly immunogenic and not associated with obesity. A mechanistic understanding of how exercise slows tumor growth is important because it will inform the design of clinical trials to determine which exercise regimens are most likely to benefit a particular tumor type based on a patient's clinical characteristics, allowing an exercise prescription to be made using precision medicine approaches. Arguably more importantly, studies in this vein may reveal new therapeutic targets for lung cancer by modulating metabolism in combination with standard-of-care treatments. In this proposal, we will examine how exercise slows lung cancer growth in mice, with the Overarching Hypothesis that the beneficial effects of exercise on lung cancer progression result from a combination of systemic metabolic interactions linking muscle to the immune system to the tumor. We anticipate that exercise both reduces tumor glucose uptake, and increases immune cell glucose and fatty acid metabolism, thereby enhancing T cell activation, and preventing exhaustion. These hypotheses will be tested using a complement of tissue-specific knockout mice, methods that we developed to model tissue-specific substrate metabolism, and multiple exercise modalities mimicking low- intensity exercise as well as high-intensity interval training. In so doing, we anticipate generating new insights into how muscle-tumor-T cell interactions mediate the beneficial effects of exercise in immunogenic tumors, and may identify new immunometabolic targets to enhance the efficacy of exercise, generating an evidence-based exercise prescription for lung cancer in mice.