Project 1: Mechanisms of alloreactivity modulation by intestinal microbiota

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Hypothesis: Elements within the gut microbiome modulate systemic immune responses that are important for cancer immunotherapy. We will dissect this in mouse models of GVHD and in anti-tumor mouse models driven by checkpoint blockade drugs under various microbiome manipulations. Parallel experiments will make use of the same mouse models to test hypothesis that fecal microbiotas from patients will exacerbate disease using complete human fecal communities, either as viably preserved whole stool, consortia reassembled from fecal culture collections, or sterile filtrates. 

 

 

Project 2: Defining key immunologically relevant bacterial metabolites

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Hypothesis: Products of bacterial metabolism are the main way by which commensal organisms influence host immune functions. We have assembled a sterile-filtered panel of bacterially derived metabolites that are enriched in mouse cecal contents of specific-pathogen-free mice as compared with germfree controls. These individual metabolites will be screened in a variety of in vitro assays to identify bacterial metabolites that modulate immune function. Candidate hits from this screen will be confirmed in dose-response experiments before proceeding to mechanistic analyses of the effect of the molecule on the cell of interest and evaluation of effects on disease models in vivo.

 

 

Project 3: To develop clinically useful, rapid-turnaround biomarker panels to identify patients with (a) microbiota injury and who are at risk of deleterious clinical outcomes and (b) compositions that predict response of tumors to checkpoint-blockade therapy.

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Sequencing-based profiling of the fecal microbiota requires several weeks and is therefore not readily amenable to clinical practice or to assigning patients to clinical trials of microbiome manipulation. To facilitate clinical implementation of microbiota discoveries, we will develop a biomarker panel that assesses the health of the microbiota using multimodality approaches.