PROJECT SUMMARY/ABSTRACT Cachexia negatively impacts the response to therapies and clinical outcomes of cancer patients and is indirectly responsible for approximately 20% of cancer-related mortality. Cancer-associated cachexia is characterized by dramatic loss of body weight, skeletal muscle mass, and systemic inflammation. This manifests as greater perceived exertion, increased muscle fatigue, and reduced quality of life. Strong experimental evidence supports the inclusion of exercise during and after cancer treatment to maintain or improve physical function, fatigue, and survival. However, exercise is often difficult for cancer patients and a pharmacologic strategy to mimic exercise responses and adaptations represents a feasible alternative to exercise for patients to offset cancer-associated fatigue. The immunomodulatory cytokine, interleukin-15 appears in the circulation transiently after exercise. Increases in circulating IL-15 are associated with a greater exercise capacity as well as a fatigue-resistant muscle phenotype due to an increase in mitochondrial density. These effects occur in addition to the well-known roles of IL-15 within the immune system, which include effects on Natural Killer cells and CD8 T cells. Therefore, IL-15 represents a potentially important mechanistic link for the ability of exercise to positively impact patient survival after a cancer diagnosis. Given these findings, there is a critical need to develop therapeutic strategies to increase circulating IL-15 in cancer patients to take advantage of its dual roles in the immune system and in skeletal muscle. The objective of this application is to identify the mechanisms by which IL-15 affects tumor growth and attenuates muscle fatigue associated with cancer. Our central research hypothesis is that greater IL-15 in the circulation will impede tumor growth through enhancement of lymphocyte infiltration into tumors as well as attenuate cancer- associated muscle fatigue through stimulation of mitochondrial biogenesis. Three Specific Aims have been designed to test this central hypothesis. Specific Aim 1 will test the hypothesis that greater circulating levels of IL-15 will alter the tumor microenvironment by promoting lymphocyte infiltration into tumors, thus initiating a latency of tumor development. Specific Aim 2 will test the hypothesis that greater circulating levels of IL-15 will attenuate cancer-associated muscle fatigue through stimulation of mitochondrial biogenesis. Specific Aim 3 will test the hypothesis that breast cancer down-regulates IL-15 signaling that is linked to mitochondrial biogenesis within skeletal muscle. The rationale for the proposed research is that, once these mechanisms of action of IL-15 are detailed with respect to tumor growth inhibition and muscle fatigue attenuation, new and innovative IL-15-based therapies can be developed to treat cancer-related morbidity and mortality. The knowledge gained from this project will have a positive impact on cancer patient survival through the development of innovative therapies targeting tumor growth and muscle dysfunction.