(535g) Reprogramming Innate Immune Cells to Probe and Modulate Immunosuppressive Tumor Microenvironments

Harnessing the immune system to control cancer is an attractive prospect, yet it has proven difficult to implement. Although recent advances in immunology have enabled such technologies as patient- and tumor-specific cancer vaccinations and related immunotherapies, which have shown great promise in preclinical experiments, clinical benefits typically remain quite limited. It is now recognized that a major obstacle to the therapeutic efficacy of many such approaches is tumor-mediated immunosuppression in local microenvironments. Moreover, the mechanisms by which these multicellular networks form and are sustained remain poorly understood. Our long-term goal is to build cellular therapies that safely and effectively break down these immunosuppressive local environments in order to enhance the clinical efficacy of immunotherapies targeting a broad spectrum of cancers. To achieve this, we employ the tools of synthetic biology to build new genetic programs into cells of the innate immune system, including dendritic cells (DCs) and macrophages (MPs).

Here, we will discuss our work aimed at understanding the roles of cytokine receptor signaling and cross-talk between signaling pathways (including those of pattern-recognition receptors, such as the Toll-like receptors), in the functional polarization of innate immune cells. Both DCs and MPs are capable of taking on multiple functional roles in guiding immune function, including both immunosuppressive and immunostimulatory phenotypes. This seeming contradiction arises because these cells play important roles in both protective immunity and maintaining normal homeostasis. We employ quantitative experimental and computational tools to dissect the process by which DCs and MPs integrate a multitude of cues from their environments in order to commit to one functional polarization or another. In particular, we utilize engineered cytokine receptors and pathways, real-time and single-cell measures of gene expression, and mechanistic molecular modeling and simulation. Questions under investigation include (1) How is functional polarization determined under conditions of incoherent inputs (for example, in a mixture of pro- and anti-inflammatory cytokines)? (2) What is the role of stochastic variability in these processes? and (3) What are the requirements for sustaining or destabilizing immunosuppressive networks? This work both enhances our understanding of fundamental tumor immunology and informs the design of therapeutic interventions, which we are working to implement and evaluate.