Reprogramming brain immunosurveillance with engineered cytokines

Abstract

Immune surveillance of the brain is regulated by resident non-neuronal cells and the blood-brain barrier. Dysregulation of immunosurveillance is a hallmark feature of several diseases including brain tumors that interact with and rely heavily on immune cells, suggesting that disrupting the neuroimmunology of tumors could slow their progression. Yet few tools are available to control brain immunology in vivo with local precision, and fewer yet are used for therapeutic intervention. Here, we propose engineered cytokines as a neuroimmune-modulation platform. We demonstrate that the residence time of cytokines in the brain can be tuned by binding them to the extracellular matrix or synthetic scaffolds. We then show that the aluminum hydroxide adjuvant (alum) is retained in the brain >2 weeks. Tethering of inflammatory cytokines such as interleukins (IL) 2 and 12 to alum yields extended neuroinflammation and brain immunosurveillance after intracranial administration, while avoiding systemic toxicity. In mouse models of both immunologically hot and cold brain tumors, the intracranial deposition of alum-tethered cytokines causes significant delay in tumor progression. RNA profiling reveals that engineered cytokines engage both innate and adaptive immunity in the brain. These findings suggest that engineered cytokines can reprogram brain immunosurveillance, informing the development of future therapies for neuroimmune diseases.

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“…The biorxiv preprints propose the use of aluminum hydroxide adjuvants to retain drugs in brain tumors, which are difficult to use for immune impacts with local precision [ 135 ]. In mouse models of both immunologically hot and cold brain tumors, the intracranial deposition of alum-tethered cytokines has been shown to cause significant delay in tumor progression vs. alum alone.…”

“…They engage both innate and adaptive immune mechanisms, as well as preserve neuronal function and dynamics by promoting the immune surveillance of tumors. The brain tissue of mice carrying tumors—treated with cytokines bound to alum—was enriched by the expression of genes consistent with healthy brain function, including genes involved in carbohydrate or lipid metabolism, which are similar to the brain tissue from a naïve subject [ 135 ].…”