Immunomodulatory impact of the gut microbiome on tumor progression - Project Summary The human gut microbiome is comprised of bacteria and other microorganisms that inhabit the gastrointestinal tract and play a pivotal role in host health. Recent studies have shown the contributing role of the gut microbiome to outcomes of immunotherapy, specifically immune checkpoint inhibition. In a promising phase I clinical trial, fecal microbiome transplantation from a patient that is responsive to immune checkpoint inhibition into immunotherapy resistant patients improved their responsiveness to treatment. This novel approach for cancer therapy highlights the potential of therapies that can target the immunomodulatory role of the gut microbiome on the host. Despite early clinical success, we still lack the understanding of the underlying mechanisms driving these microbiome effects. Therefore, the goal of this project is to investigate the mechanisms behind the immunomodulatory role of the gut microbiome in cancer by looking at effector molecules produced by the gut microbiome and their bioactivities. The hypothesis driving this work is that the gut microbiome produces bioactive molecules that slow down tumor progression by modulating the host immune system. Preliminary results in a mouse model of melanoma wherein germ-free mice were colonized with six healthy human gut microbiomes shows substantial variability in baseline tumor growth independently from immunotherapy. In preliminary immune characterization, donor microbiome-colonized mice with the slowest tumor progression show increased frequency of interferon gamma expressing cytotoxic T cells in tumor-infiltrating lymphocytes. I designed a study that combines two complimentary aims that utilize host-centric and microbiome-centric approaches. Aim 1 will characterize immune cell populations altered by the gut microbiome during tumor progression. In tumor bearing mice harboring human gut microbiomes, I will profile systematic and tumor-specific immune changes and quantify the expression of immune cell activation and exhaustion markers. Aim 2 will identify gut microbiome- derived bacterial products that impact tumor-immune crosstalk. I will utilize cellular assays that probe tumor- immune cell interactions to test: (a) bacterial strains enriched in patient cohorts that underwent immunotherapy, (b) small molecules produced by ex vivo cultures of donor microbiomes, (c) bacterial metabolites from donor- colonized mice. Completion of the proposed work will provide a foundation to develop innovative microbiome targeted adjuvant therapies for cancer patients. By utilizing the combined expertise of two leading labs in the fields of cancer molecular biology and host-microbiome interactions, this study will provide novel insights into the crosstalk between the tumor cells, immune cells, and the gut microbiome. Through the Rutgers Robert Wood Johnson Medical School and Princeton University MD/PhD program, I will learn cutting-edge techniques in cancer research, develop my academic communication skills, form a network of scientist and clinician mentors, and integrate my research and clinical training. My personalized professional development plan sets me on the right track to enter a research track residency and become an independent physician scientist.
