Vaccines are vital tools in the healthcare arsenal. The best vaccines agonize synergistic combinations of immune receptors, resulting in the life-long protective response in the patient. Unfortunately, we do not know which combinations of immune receptor activation to direct the particular immune response that gives rise to life-long immunity. We aimed to discover the mechanism of immune receptor synergies by elucidating their effects on intra- and intercellular pathways affecting gene expression and multicellular communication. To elucidate these pathways, we wanted to create a tool to select and isolate single cells in order to understand the contribution of individual cells to the population response. To enable this analysis, core-shell microparticles were synthesized via size-controlled polymerization of polystyrene cores, followed by encasement in a silica-silane copolymer shell. This shell is advantageous for two main reasons: 1) it passivates the microparticle surface to background immune activation; 2) it provides functional groups for small molecule attachment.  Immune agonists and fluorophores were then appended using a heterobifunctional PEG crosslinker. Cells that have engulfed the microparticles are then separated with FACS, and analyzed in bulk by microscopy, immunohistochemistry, and qRT-PCR. Sorted cells are further subjected to single-cell transcriptomic and epigenetic analyses. Autocrine vs. paracrine signaling effects are probed in order to gauge the effects of micro-environmental cues on immune cell response. These results provide insight into the precise origin of agonist synergies at a single- and multicell level. This knowledge may allow us accelerate vaccine discovery and development, and bring the possibility of tailoring vaccines against personalized targets–such as tumor cells–within reach.

Discovering the cellular origin of agonist synergies towards the development of better vaccines

253rd National Meeting (2017)

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