Utilizing interleukin-15 to target tumor microenvironment and muscle fatigue during cancer

项目摘要/摘要 恶病质对癌症患者的治疗反应和临床结果有负面影响 间接造成约20%的癌症相关死亡。癌症相关的恶病质是 以体重、骨骼肌群和全身炎症为特征的。这 表现为更大的体力消耗，肌肉疲劳增加，生活质量下降。强壮 实验证据支持在癌症治疗期间和之后进行锻炼以保持或 改善身体机能、疲劳感和生存能力。然而，运动对癌症患者来说往往是困难的，而且 模拟运动反应和适应的药物策略是一种可行的替代 为患者进行运动，以抵消与癌症相关的疲劳。免疫调节细胞因子白介素15 在运动后短暂地出现在循环中。循环中IL-15的增加与更大的 由于线粒体密度的增加，运动能力以及耐疲劳的肌肉表型。 这些影响是除了众所周知的IL-15在免疫系统中的作用之外发生的，包括 对自然杀伤细胞和CD8 T细胞的影响。因此，IL-15代表了一种潜在的重要机制 运动的能力对癌症诊断后患者的生存有积极影响。考虑到这些 研究发现，迫切需要开发治疗策略来增加癌症患者循环中的IL-15 以利用其在免疫系统和骨骼肌中的双重作用。这样做的目的是 应用是确定IL-15影响肿瘤生长和减轻肌肉疲劳的机制 与癌症有关。我们的中心研究假设是，循环中较高的IL-15会阻碍 通过增强淋巴细胞对肿瘤的渗透来促进肿瘤的生长，以及减轻癌症- 通过刺激线粒体生物发生而引起的肌肉疲劳。三个具体目标是 旨在检验这一中心假说。具体目标1将检验以下假设：更大的循环水平 IL-15将通过促进淋巴细胞向肿瘤的渗透而改变肿瘤的微环境，从而启动一种 肿瘤发展的潜伏期。特定目标2将检验以下假设：更高的循环IL-15水平将 通过刺激线粒体生物发生来减轻癌症相关的肌肉疲劳。具体目标3 将检验乳腺癌下调与线粒体有关的IL-15信号的假说 骨骼肌内的生物发生。提出这项研究的理由是，一旦这些机制 IL-15在抑制肿瘤生长和减轻肌肉疲劳方面的作用详细，新的和 可以开发基于IL-15的创新疗法来治疗癌症相关的发病率和死亡率。这个 从这个项目中获得的知识将通过 开发针对肿瘤生长和肌肉功能障碍的创新疗法。

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.