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.