Broad Prophylaxis of Infectious Disease and Cancer via Trained Immunity
Recent work has revealed that innate immune cells have a non-specific form of memory, referred to as “trained immunity” (TI). Trained immunity is characterized by epigenetic and metabolic remodeling that result in improved responses to pathogens. Training the innate immune system improves organism survival against lethal infections or cancer challenges. Current models of trained immunity focus on macrophages and use β-glucan or Bacillus Calmette–Guérin (BCG) vaccines to induce training, both of which are limited in their therapeutic applications.
In the Esser-Kahn Lab, we seek to improve our understanding and control of trained immunity through (1) improved nanoparticle-based delivery of trained immunity inducers, (2) high throughput screening of new small molecule trained immunity drugs, and (3) harnessing trained immunity as a prophylactic therapeutic.
Recently, our lab reported that encapsulated β-glucan in PLGA nanoparticles allows for temporal control over trained immunity, widening the time window of its therapeutic effects. Release profiles of these β-glucan nanoparticles can be modulated by altering the PLGA polymer chemistry, and slow release was found to widen the time window of β-glucan’s therapeutic effects. This method of innate immune training also exhibited improved resistance to cancer growth in a melanoma model (https://doi.org/10.1002/adhm.202200819).
Temporal control of trained immunity via β-glucan encapsulated in PLGA nanoparticles
We are also using high throughput screening to identify small-molecule inducers of trained immunity. Small molecules may exhibit improved pharmacokinetic and safety profiles over traditional inducers of training, which are chemically complex and derived from inconsistent biological sources. Novel small molecule inducers may trigger trained immunity through previously unknown pathways that result in similar epigenetic and metabolic effects as BCG and β-glucan, furthering our understanding of the training phenomenon. These molecules can be applied as prophylactics in models of cancer and lethal infection.