Bioelectronic Neuroimmune Interfaces for Studying Brain Tumors

The nervous and immune systems are intimately related in the brain and in the periphery. Immune cells secrete and present receptors for neurotransmitters, and neurons secrete and present receptors for immuno-modulatory cytokines. Immune cells are responsible for sculpting and pruning neuronal synapses, and neurons can dampen or amplify an innate or adaptive immune cascade. Diseases in the brain, such as brain tumors, interact with and rely on both neurons and immune cells, suggesting that disrupting the underlying neuroimmunology of tumors could slow their growth and improve patient clinical outcomes.<br/><br/>Yet there are few tools to study or control neuroimmune interactions chronically <i>in vivo</i>. By combining a neuro-modulation platform with an immune-modulation platform, we demonstrate an engineered Bioelectronic Neuroimmune Interface (BNI). We combine soft, hydrogel-based bioelectronic neural interfaces¹ with engineered cytokines for cancer immunotherapy² to enable simultaneous control of neurons and immune cells in the brain. We demonstrate these BNIs can optically, electrically, and chemically modulate both neurons and immune cells. Using protein engineering, we create immunomodulatory cytokines with customizable residence times. By tuning this residence time and identity of the cytokine, we demonstrate cell-specific spatiotemporal control of the brain’s immune environment. In addition to convection-driven transport of neuro- and immuno-modulatory compounds through the microfluidic channel, we also demonstrate that drugs can be loaded and released with a distinct diffusion-based release profile through the hydrogel cladding itself.<br/><br/>Finally, we show BNIs can be adapted to directly interface with brain tumors. Utilizing a piggyBac transposon/transposase system, we create stable GCaMP6s+ and ChR2+ tumors and demonstrate that BNIs can chronically probe or modulate tumor growth and cell depolarization <i>in vivo</i>. We also show that neurons near a tumor can be depolarized utilizing a one-step or two-step optogenetics approach in the presence of established brain tumors. These capabilities enable experiments for interrogating the cancer-neuron axis³ chronically <i>in vivo</i> and open up the way for screening new neuro-immune therapies for combating aggressive adult brain tumors.<br/><br/>¹Tabet et al, <i>ACS Central Science </i>(2021). ²Agarwal et al, <i>Nat Biomed Eng</i> (in press). ³Monje et al, <i>Cell </i>(2020).