The tumor microenvironment (TME) is the ecosystem surrounding cancer cells. It consists of various innate and adaptive immune cells, cancer-associated fibroblasts, vascular cells, and nerves. Notably, the outcome of cancer immunotherapy is strongly associated with many immune-specific markers in the TME, regarding M1/M2 macrophages, dendritic cell subsets, CD8+ T cell to regulatory T cell ratio, and expression of co-stimulatory/co-inhibitory molecules. Previous reports including our publication and our preliminary data suggest that gut commensal microbes shape the immune landscape in the TME. However, how gut microbes regulate these cellular processes is not well-defined. The first direction of our studies is to dissect the signaling mechanisms by which specific gut microbes regulate immune cells in the TME. We aim to identify signaling receptors and mediators that link gut microbial signals to changes in tumor-infiltrating immune cells such as PD-L2/RGMb modulation that we have reported. Additionally, our lab is interested in the molecular and cellular mechanisms by which these signaling pathways modulate T cell responses. We will further examine whether the commensal-dependent immune mechanisms play an important role in other contexts, such as chronic viral infection.

Commensal microbes produce a multitude of immunomodulatory molecules, including bacterial surface compounds and extracellular metabolites. This diverse array of signaling molecules can alter the differentiation processes and functions of intestinal immune cells. Despite evidence of bacterial metabolites in the circulatory system and their involvement in regulating anti-tumor immunity, we have limited knowledge of bacterial metabolites and their derivatives in the TME. Addressing this knowledge gap will broaden our understanding of immune regulation by microbial components in the TME and potentially identify novel therapeutic agents produced by bacteria. Our research group examines gut microbial metabolites in tumors and determine their immunological roles in the TME. We first approach this project with a particular focus on lipids and glycerol, which previous publications and preliminary findings have identified as important in regulating immune cells and cancer cells. As a member of the Cancer Metabolomics Center, we characterize and identify gut microbe-derived metabolites using metabolomic approaches. In collaboration with the Yao Lab at the University of Chicago (Yao, Park, 2023, Mol Cell; manuscript submitted), we also study the role of glycerol metabolism in regulating T cell-mediated immunity in the context of the microbiome. Our ultimate goal is to engineer bacteria to produce desirable molecules that enhance anti-tumor immunity and to develop methods for delivering these molecules to the tumor microenvironment (TME).