Defining how obesity shapes immunity and the success of cancer immunotherapy

定义肥胖如何影响免疫力以及癌症免疫治疗的成功

• 批准号: 10449321
• 负责人: Ryan M Teague
• 金额: $ 33.96万
• 依托单位: SAINT LOUIS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10449321
• 关键词: Adipose tissue; Affect; American; Animal Experiments; Animal Model; Animals; Body mass index; CD8-Positive T-Lymphocytes; CD8B1 gene; Cancer Patient; Cardiovascular Diseases; Cell physiology; Cells; Collection; Complex; Conflict (Psychology); Data; Development; Disease; Epidemic; Failure; Functional disorder; Future; Goals; Health; Human; Immune; Immune System Diseases; Immune response; Immunity; Immunosuppression; Immunotherapy; Impairment; Individual; Infection; Inflammation; Link; Malignant Neoplasms; Manuscripts; Measures; Metabolism; Modeling; Mus; Obese Mice; Obesity; Obesity Epidemic; Outcome; Pathway interactions; Patient-Focused Outcomes; Patients; Persons; Population; Research; Resistance; Risk; Role; Serum; Shapes; T-Lymphocyte; Testing; Therapeutic; Tissue Sample; Translating; Translational Research; Tumor Immunity; Vaccines; Variant; cancer immunotherapy; cancer therapy; cancer type; comorbidity; effector T cell; fatty liver disease; functional restoration; high risk; human tissue; immune checkpoint blockade; immune function; immune resistance; innovation; insight; lipidomics; liver function; melanoma; metabolomics; mouse model; patient subsets; pre-clinical research; preclinical study; response; success; tumor; tumor growth

NCI Provocative Question #2: “How do variations in immune function caused by comorbidities or observed among different populations affect response to cancer therapy?” The success of checkpoint blockade immunotherapy and its role in the future of cancer treatment is now beyond debate, but durable responses still only occur in a subset of patients. Extending the success of immunotherapy to a broader range of patients requires new insight into the variables that dictate therapeutic success and failure. More than a third of Americans are now considered obese, a condition associated with impaired immune responses to infections and vaccines, and a greater risk of developing some types of cancer. This implies a potential link between obesity and poor tumor immunity, which has been documented in a few preclinical studies but mechanistic insight remains sparse. More importantly, efforts to understand how obesity influences outcomes in human cancer patients has been mired by conflicting results and limited metrics such as body mass index (BMI) to measure obesity in people. These inconsistencies have contributed to the controversial “obesity paradox”, which suggests that obesity has a positive impact on outcomes for patients with cancer, cardiovascular disease or a host of other ailments, but this idea is facing mounting skepticism. Our preliminary research in a mouse tumor model refutes the obesity paradox, identifying obesity as a barrier to the success of cancer immunotherapy. Here, obesity was associated with poor control of melanoma tumor growth following checkpoint blockade immunotherapy, associated with dysfunction of tumor infiltrating T cells. We hypothesize that obesity-related comorbidities such as excessive adipose tissue, inflammation, altered metabolism and liver function compromise immunotherapy by suppressing the functional restoration of T cells. To test this, we will employ several innovative mouse models that allow discrete manipulation of T cell effector pathways (Aim 1), excessive adiposity and the development of fatty liver disease (Aim 2). These mechanistic studies will enable the contributions of individual comorbidities to be rigorously dissected. We predict that results from these animal experiments will enable parallel discoveries in cancer patients (Aim 3), revealing the critical components of human obesity that influence outcomes during cancer immunotherapy. Our goal is to define the complex obesity-related factors that shape immune responses to cancer and influence outcomes during cancer immunotherapy. Given the magnitude of the obesity epidemic, our translational research has the potential to benefit a significant number of cancer patients for whom current immunotherapies may have limited efficacy and require refined treatment approaches.

NCI挑衅性问题#2：“如何观察到由合并症引起或观察到的免疫功能的变化 会不会影响不同人群对癌症治疗的反应？“ 检查点阻断免疫疗法的成功及其在未来癌症治疗中的作用现在已经超出了 虽然有争论，但持久的反应仍然只发生在一小部分患者身上。扩大免疫治疗的成功 对于更广泛的患者，需要对决定治疗成败的变量有新的见解。 超过三分之一的美国人现在被认为是肥胖，这是一种与免疫力受损有关的疾病 对感染和疫苗的反应，以及患某些类型癌症的风险更大。这意味着一个 肥胖和肿瘤免疫力低下之间的潜在联系，已经在一些临床前研究中得到了证明 但机械论的洞察力仍然稀少。更重要的是，努力了解肥胖是如何影响结果的 人类癌症患者的研究一直受到相互矛盾的结果和有限的指标(如体重指数)的困扰 (BMI)来衡量人们的肥胖症。这些不一致导致了备受争议的“肥胖” 矛盾“，这表明肥胖对癌症、心血管疾病患者的预后有积极影响 疾病或许多其他疾病，但这一想法正面临越来越多的质疑。 我们在小鼠肿瘤模型中的初步研究驳斥了肥胖悖论，认为肥胖是 癌症免疫治疗的成功。在这里，肥胖与黑色素瘤控制不良有关。 检查点阻断免疫治疗后的生长，与肿瘤浸润性T细胞功能障碍相关。 我们假设肥胖相关的合并症，如脂肪组织过多，炎症， 新陈代谢和肝功能通过抑制T细胞的功能恢复而影响免疫治疗。 为了测试这一点，我们将采用几种创新的小鼠模型，允许离散操作T细胞效应器 途径(目标1)、过度肥胖和脂肪肝的发展(目标2)。这些机械式的 研究将使人们能够严格剖析个体合并症的贡献。我们预测结果是 这些动物实验将使癌症患者的平行发现成为可能(目标3)，揭示了关键的 在癌症免疫治疗期间影响结果的人类肥胖的组成部分。 我们的目标是定义复杂的肥胖相关因素，这些因素塑造了对癌症的免疫反应，并影响 癌症免疫治疗期间的结果。鉴于肥胖症流行的规模，我们的翻译研究 有可能使相当数量的癌症患者受益，目前的免疫疗法可能对这些患者有 疗效有限，需要改进治疗方法。