The microbiome in older adults with lung cancer: association of treatment regimens and diet with protective microbial profiles

项目总结 肠道微生物群随着人类年龄的增长而变化，并影响人类健康的许多方面，包括对 癌症治疗。微生物阿克曼氏菌丰度的增加已经显示出增加了 对免疫检查点阻断的反应(ICB)，一类抗癌药物使免疫系统能够 识别和攻击癌细胞。合理操作微生物组是一种很有前途的改进方法 癌症和其他健康后果，但与许多研究和试验一样，年龄的影响还没有得到充分研究。更老的 成人在ICB的临床试验和针对微生物组的干预措施中的代表性仍然很低 促进对ICB的回应。这是有问题的，因为年龄已经被证明会影响微生物群。 因此，与微生物组相关的干预很可能必须针对老年人量身定做。此外, 基于饮食的微生物组干预很可能进入临床实践，但将食物摄入量与 事实证明，特定的微生物具有挑战性。 我的总体目标是成为一名研究微生物群在癌症治疗中的作用的学术研究员 老年人，以及如何使用以饮食为基础的干预措施来修改老年人的微生物群，以促进 健康。为此，本申请的目的是(1)确定老年人的微生物群 应对ICB，(2)通过基于饮食的干预措施修改微生物组，以及(3)验证 使用临床前模型的微生物组。为了实现这些目标，这项研究将利用正在进行的数据 我领导的微生物组收集、数据生成和分析工作的试验。首先，这些数据 将有助于确定对ICB(SA1)有反应的老年肺癌患者的微生物群。接下来，我们将测试一个 黑覆盆子饮食干预对老年人促进ICB反应前微生物群的作用 (SA2)。最后，将干预前后的人体微生物群转移到小鼠体内，以评估效果。 关于对ICBS的反应(SA3)。 这些目标将支持一种预测哪些老年人对治疗有反应的方法，建议 延长健康寿命的治疗策略，并提高我们对微生物群如何相互作用的理解 与老年人的免疫系统有关。这个奖项将为我提供时间来收集知识和 在我目前培训之外的领域，特别是临床老年病学和癌症微生物组方面的经验。我的 导师团队包括这些领域的专家以及营养、肿瘤学和计算建模方面的专家。 在这些专家和有针对性的教学人员的全力支持下，我相信这个奖项将加速我的 过渡到一个独立的调查员。

PROJECT SUMMARY The gut microbiome changes as humans age and affects many aspects of human health including response to cancer treatments. Increased abundance of the microbe Akkermansia muciniphila has been shown to increase response to immune checkpoint blockade (ICB), a class of anti-cancer agents enable the immune system to identify and attack cancer cells. Rational manipulation of the microbiome is a promising approach to improve cancer and other health outcomes, but as with many studies and trials, the effect of age is understudied. Older adults remain poorly represented in clinical trials for ICB and interventions directed at the microbiome to promote response to ICB. This is problematic because age has been shown to affect the microbiome. Therefore, an intervention related to the microbiome will likely have to be tailored to older adults. In addition, diet-based microbiome interventions are likely to enter clinical practice, but linking food intake to changes in particular microbes has proven challenging. My overall goal is to be an academic researcher studying the role of the microbiome in cancer care for older adults, and how to use diet-based interventions to modify the microbiomes of older adults to promote health. To this end, the objectives of this application are (1) identify the microbiomes of older adults who respond to ICB, (2) modify the microbiome through diet-based interventions, and (3) verify the causal role of the microbiome using preclinical models. To meet these objectives, this study will utilize data from ongoing trials for which I am leading the microbiome collection, data generation and analysis efforts. First, these data will help to define the microbiomes of older lung cancer patients who respond to ICB (SA1). Next, we will test a black raspberry dietary intervention for its ability to promote a pro-ICB response microbiome in older adults (SA2). Finally, pre- and post-intervention human microbiomes will be transferred into mice to assess the effect on response to ICBs (SA3). These aims will support a method for predicting which older adults will respond to treatment, suggest a therapeutic strategy to increase healthspan, and improve our understanding of how the microbiome interacts with the immune system in older adults. This award will provide me with the time to gather knowledge and experience in fields outside my current training, especially clinical geriatrics and the cancer microbiome. My mentorship team includes experts in these fields as well as in nutrition, oncology, and computational modeling. With the dedicated support of these experts and targeted didactics, I believe this award would accelerate my transition to an independent investigator.