Friday, May 23, 2025
5/23/2025
Modulating Human Microbiome Function to Enhance Immune Responses Against Cancer - PROJECT SUMMARY Cancer immunotherapy has been one of the great recent breakthroughs in cancer treatment options. Antibodies that antagonize immune-inhibitory receptors, a therapy type known as immune checkpoint blockade (ICB), show great promise and further improvements in response rates and durability are likely with additional research. The potency of this cancer therapy demonstrates its incredible potential, and yet for most cancer patients these amazing benefits are currently unattainable. One current challenge in checkpoint blockade therapies is understanding the highly variable responses across patient cohorts. The gut microbiome, a major source of interindividual biological variability, is known to impact systemic immune status and specific features of microbiome composition have been linked to ICB in multiple human studies. Tests of causality in animal models of ICB have confirmed that addition of certain bacterial species to the gut microbiome induces improved tumor control. However, inconsistencies of implicated microbial species between studies and the lack of insight into molecular mechanisms that underlie the microbiome’s impact on response leave a large gap in understanding. The central hypothesis of this proposal is that discrepancies in findings between studies that focus on compositional associations are explained by a shared functional basis within phylogenetically distinct taxa. Since functions encoded by the gut microbiome are the mediators of interactions with the host, and are often shared between unrelated bacteria, a function-focused approach to study the microbiome’s effect on ICB is needed. This proposal addresses field-wide challenges in pursuing microbiome function by leveraging a broad array of tools that have been developed for the purposes of investigating microbiome functions and understanding mechanistically how they impact host biology. The goal is to identify bacterially encoded functions that enhance response to ICB. Aim 1.1 proposes metagenomic data aggregation and analysis across immunotherapy studies to identify genes associated with ICB response; the cutting-edge data analysis pipeline applied to all available data addresses previous limitations like study specific analysis choices and small cohort sizes. In Aim 1.2, isogenic pairs of bacteria that do or do not express the genes of interest will be genetically engineered; function and phenotypic differences will be characterized in culture. Aim 2 will test the impact of candidate genes/functions by colonizing a mouse model of cancer with one of each pair of isogenic bacteria and comparing ICB-mediated tumor control. In cases where microbial genes/functions enhance ICB mediated tumor control, microbiome focused metabolomics and immunological characterization of gut, tumor, and other immune compartments will provide insight into immune mediators of the effect. Definitive identification of microbiome encoded functions and mechanistic connections that determine gut microbial impact on ICB will inform individualized therapeutic suitability and enable the development of therapies that augment ICB.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).