Employing Humanized Microbiome Mice to Understand Immune Activation and Translational Therapeutic Potential in Glioblastoma - PROJECT SUMMARY The composition of the gut microbiome has been shown to determine responsiveness or resistance to immune checkpoint inhibitors (ICI), such as anti-PD-1, in patients with melanoma and other cancers. Unfortunately, although immunotherapy works well in glioblastoma (GBM) pre-clinical mouse models, the therapy has not demonstrated efficacy in humans. Most pre-clinical cancer studies have been done in mouse models using mouse gut microbiomes, but there are significant differences between mouse and human microbial gut compositions. To address this anomaly, we developed a novel humanized microbiome (HuM) model to study the response to immunotherapy in a pre-clinical mouse model of GBM. We have recently published that various human microbiome compositions can dictate the efficacy of T-cell ICIs (anti-PD-1) in a pre-clinical GBM model. We are the first to report that human microbiota affects T-cell ICI response in mouse models of GBM, indicating that for patients with GBM, there may be beneficial microbes that can increase efficacy of ICIs. Furthermore, the largest portion of immune cells in GBM are tumor associated macrophages and microglia (TAMs). To date, no studies have examined the role of the microbiome in response to TAM targeted therapies, such as CSF1R inhibition or anti-CD47, in GBM. In addition, the question still remains of whether the “responsive” microbial communities in can be therapeutically exploited to rescue resistance to therapies, or if the “resistant” microbial communities in can be depleted and/or replaced. We have identified “responder” or optimal human microbiome compositions, as well as “non-responder” or resistant human microbiome compositions in our pre-clinical GBM models, which have also been confirmed in a melanoma model. We hypothesize that responder microbiome communities promote a heightened baseline level of anti-tumor inflammation, which helps stimulate the efficacy of immunotherapy in GBM. Using our novel humanized microbiome mouse model, this proposal seeks to uncover the human microbial- immune mechanisms of response to immunotherapies in GBM pre-clinical models, including T-cell (Aim 1) and TAM (Aim 2) mediated effects, and assess if responder microbiomes can be exploited and used therapeutically. Overall, we seek to enhance our understanding of the role of human microbiota in innate and adaptive immune-microbial interactions, and to demonstrate the translational potential of responder “optimal” microbiomes.
