Modular cell-based biosensors for dynamically imaging immune function in vivo

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Nichole Daringer, Josh Leonard, Rachel Dudek

Northwestern University, United States

The ability to dynamically monitor or visualize local immune states in vivo would transform our ability to understand processes such as the establishment and development of dysfunctional immune states at tumor sites and the response of these multicellular networks to potential therapeutic interventions. To date, however, we are limited to systemic measures (such as profiles of serum cytokines or circulating immune cells) or terminal assays (requiring tissue biopsy or, more commonly, sacrifice of the experimental animal). We have established a novel mammalian synthetic biology technology enabling us to engineer cells into living “biosensors” responsive to environmental stimuli that are exclusively extracellular, such as the cytokines that characterize specific immunological states. These cell-based biosensors detect a relevant analyte of interest and then produce an optical signal that can be imaged in whole, living animals (e.g., luminescence, near-infrared fluorescence). This approach is fundamentally distinct from a reporter gene approach, in which one can only detect whether a given gene is expressed in the engineered cell, not whether the engineered cell is exposed to the analyte. The platform and its components are orthogonal from native signaling components and can be adapted to detect many different extracellular signals allowing the potential for multiparametric evaluation of the extracellular microenvironment. As an initial proof of principle, we will engineer tumor cells to function as biosensors, such that following adoptive transfer of engineered tumor cells to a syngeneic mouse host, the tumor will monitor and report upon its own immunological milieu. We will initially be applying this technology to help understand how the immune response shifts from anti-tumor (immunostimulatory) to pro-tumor (immunosuppressive) during the course of tumor progression. This foundational technology could eventually be extended to generate cell-based therapies by tying biosensing to the expression of therapeutically-relevant gene products.