(66f) Emulating Infections for Reprogramming Local Immune Responses

Tumors and infectious pathogens evolve the capacity to manipulate host responses and induce local immune dysfunction. In particular, many primary and metastatic solid tumors induce profound immunosuppression, which impedes both natural immune clearance and interventions such as therapeutic cancer vaccination. Overcoming this barrier is widely considered a major obstacle to achieving safe and effective biological therapies for cancer. Recently, it was reported that such immunosuppression can be reversed by injecting small-molecule ligands for biosensor proteins of the innate immune system, called Toll-like Receptors (TLRs), into an established tumor. However, therapeutic utilization of this mechanism is complicated by the fact that (a) systemic administration of TLR ligands is potentially toxic and (b) local administration requires repeated (or continuous) injection of ligands into known tumor sites over an extended period of time. To overcome these limitations, we are employing the tools of synthetic biology to engineer programmable cellular devices that safely and specifically reproduce the potency of injected TLR ligands in a clinically viable fashion. In particular, we are developing genetically engineered macrophages (EMPs), that travel to tumor milieus, detect specified microenvironmental cues (e.g., elevated levels of cytokines such as IL-10 and TGF-beta), and induce potent pro-inflammatory responses (e.g., by inducing TLR-regulated gene networks). We are pursuing these goals by engineering receptor complexes (inputs), intracellular signaling and regulatory pathways (processors), and intercellular signaling mechanisms (outputs). Here we will describe the construction, characterization, and initial implementation of this novel platform for programming local immune function.