Defining how obesity shapes immunity and the success of cancer immunotherapy

NCI挑衅性问题#2：“合并症或观察到的免疫功能变化如何导致 会影响癌症治疗的效果吗？” 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越了 目前还存在争议，但持久的反应仍然只发生在一小部分患者中。扩大免疫疗法的成功 更广泛的患者需要对决定治疗成功和失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的，这是一种与免疫功能受损有关的疾病。 对感染和疫苗的反应，以及发展某些类型癌症的风险更大。这意味着 肥胖和肿瘤免疫力低下之间的潜在联系，这在一些临床前研究中已有记录 但机械论的观点仍然很少。更重要的是，努力了解肥胖如何影响结果 由于相互矛盾的结果和有限的指标，如体重指数， (BMI)来测量人们的肥胖程度。这些矛盾导致了有争议的“肥胖症 悖论”，这表明肥胖对癌症、心血管疾病和糖尿病患者的预后有积极影响。 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，将肥胖确定为 癌症免疫疗法的成功在这里，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， 代谢和肝功能通过抑制T细胞的功能恢复而损害免疫治疗。 为了测试这一点，我们将采用几种创新的小鼠模型，允许离散操纵T细胞效应子。 途径（目标1），过度肥胖和脂肪肝疾病的发展（目标2）。这些机械 这些研究将使人们能够严格地分析各种合并症的作用。我们预测结果 从这些动物实验将使平行发现癌症患者（目标3），揭示了关键的 在癌症免疫治疗过程中影响结果的人类肥胖成分。 我们的目标是确定复杂的肥胖相关因素，这些因素影响对癌症的免疫反应， 癌症免疫治疗期间的结果。考虑到肥胖流行的严重性，我们的转化研究 具有使大量癌症患者受益的潜力， 疗效有限，需要精细的治疗方法。

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.