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

项目概要 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。研究表明，微生物阿克曼氏菌 (Akkermansia muciniphila) 的丰度增加 对免疫检查点封锁 (ICB) 的反应，一类抗癌药物使免疫系统能够 识别并攻击癌细胞。合理调控微生物组是改善微生物群落的一种有前景的方法 癌症和其他健康结果，但与许多研究和试验一样，年龄的影响尚未得到充分研究。年长的 成人在 ICB 临床试验和针对微生物群的干预措施中的代表性仍然很低 促进对 ICB 的响应。这是有问题的，因为年龄已被证明会影响微生物组。 因此，与微生物组相关的干预措施可能必须针对老年人进行定制。此外， 基于饮食的微生物组干预措施可能会进入临床实践，但将食物摄入量与微生物组的变化联系起来 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学术研究员，研究微生物组在癌症护理中的作用 老年人，以及如何使用基于饮食的干预措施来改变老年人的微生物群，以促进 健康。为此，本应用的目标是 (1) 确定老年人的微生物群 对 ICB 做出反应，(2) 通过基于饮食的干预措施改变微生物组，以及 (3) 验证 使用临床前模型研究微生物组。为了实现这些目标，本研究将利用正在进行的数据 我负责领导微生物组收集、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组。接下来，我们将测试一个 黑树莓饮食干预能够促进老年人的 ICB 反应微生物组 （SA2）。最后，干预前后的人类微生物组将被转移到小鼠体内以评估效果 对 ICB 的响应 (SA3)。 这些目标将支持一种预测哪些老年人会对治疗产生反应的方法，建议 延长健康寿命并提高我们对微生物组如何相互作用的理解的治疗策略 与老年人的免疫系统。这个奖项将为我提供时间来收集知识和 在我当前培训之外的领域拥有经验，特别是临床老年病学和癌症微生物组。我的 导师团队包括这些领域以及营养学、肿瘤学和计算建模领域的专家。 有了这些专家的热心支持和有针对性的教学，我相信这个奖项将加速我的 过渡为独立调查员。

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.