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

利用 IL-15 来靶向癌症期间的肿瘤微环境和肌肉疲劳

• 批准号: 9753310
• 负责人: Emidio Edward Pistilli
• 金额: $ 26.25万
• 依托单位: WEST VIRGINIA UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9753310
• 关键词: Affect; Appearance; Attenuated; Biogenesis; Biopsy Specimen; Blood Circulation; Body Weight decreased; Breast Cancer Patient; CD8-Positive T-Lymphocytes; Cachexia; Cancer Model; Cancer Patient; Cell Count; Cell physiology; Cells; Clinical; Data; Development; Endocrine; Exercise; Exertion; Fatigue; Functional disorder; Goals; Immune system; Infiltration; Inflammation; Innovative Therapy; Interleukin-15; Knowledge; Laboratories; Link; Lymphocyte; Maintenance; Malignant Neoplasms; Mammary Neoplasms; Metabolism; Mitochondria; Molecular; Morbidity - disease rate; Mouse Strains; Muscle; Muscle Fatigue; Muscle Mitochondria; Natural Killer Cells; Outcome; Patients; Pharmacology; Phenotype; Physical Function; Proteomics; Quality of life; Research; Resistance; Role; Signal Transduction; Site; Skeletal Muscle; Structure; Testing; Therapeutic; Tissues; Transgenic Mice; Tumor-Infiltrating Lymphocytes; attenuation; base; cancer cachexia; cancer diagnosis; cancer therapy; cytokine; density; design; exercise capacity; expectation; immunoregulation; improved; innovation; malignant breast neoplasm; mortality; mouse model; muscle form; next generation sequencing; response; screening; targeted treatment; therapy design; tumor; tumor growth; tumor microenvironment

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.

项目概要/摘要 恶病质会对癌症患者的治疗反应和临床结果产生负面影响，并且 间接导致约 20% 的癌症相关死亡率。癌症相关恶病质是 其特征是体重、骨骼肌质量急剧下降和全身炎症。这 表现为更大的体力消耗、肌肉疲劳增加和生活质量下降。强的 实验证据支持在癌症治疗期间和之后进行锻炼以维持或 改善身体机能、疲劳和生存。然而，运动对于癌症患者来说往往是困难的， 模仿运动反应和适应的药理学策略是一种可行的替代方案 为患者进行锻炼以抵消癌症相关的疲劳。免疫调节细胞因子，白细胞介素 15 运动后短暂出现在循环中。循环中 IL-15 的增加与更大的 运动能力以及由于线粒体密度增加而产生的抗疲劳肌肉表型。 除了 IL-15 在免疫系统中众所周知的作用之外，还发生这些作用，其中包括 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。 运动能力对癌症诊断后患者生存产生积极影响的联系。鉴于这些 研究结果表明，迫切需要制定治疗策略来增加癌症患者的循环 IL-15 利用其在免疫系统和骨骼肌中的双重作用。此举的目的 应用旨在确定 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 IL-15 的增加会阻碍 通过增强淋巴细胞浸润肿瘤来促进肿瘤生长并减弱癌症 - 通过刺激线粒体生物发生来减少相关的肌肉疲劳。制定了三个具体目标 旨在检验这一中心假设。具体目标 1 将检验以下假设：更高的循环水平 IL-15会通过促进淋巴细胞浸润到肿瘤中来改变肿瘤微环境，从而启动 肿瘤发展潜伏期。具体目标 2 将检验以下假设：IL-15 循环水平升高将 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相关的 IL-15 信号传导的假设 骨骼肌内的生物发生。拟议研究的基本原理是，一旦这些机制 IL-15 的作用在肿瘤生长抑制和肌肉疲劳减弱方面有详细说明，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 从该项目中获得的知识将通过以下方式对癌症患者的生存产生积极影响： 开发针对肿瘤生长和肌肉功能障碍的创新疗法。