cGAS-activating lupus autoantibody for cancer immunotherapy

Abstract

AbstractCytoplasmic DNA triggers a cGAS-mediated signaling cascade that promotes an innate immune response and is potentially actionable in cancer immunotherapy. Here we show that a cytoplasmic-localizing lupus anti-DNA autoantibody activates cGAS and facilitates an immune-mediated prolongation of survival in orthotopic models of glioblastoma (GBM). Mechanistically, cellular penetration and blood-brain barrier crossing by the anti-DNA autoantibody is linked to nucleoside transport. Pulldown, knockdown, signaling, and cytotoxicity assays demonstrate autoantibody association with and activation of cGAS. In orthotopic GBM models, the autoantibody localizes to brain tumor, increases tumor CD8+ T cell content, and prolongs survival in immunocompetent but not immunodeficient mice. This work introduces the new concept of a cGAS-activating anti-DNA autoantibody, which impacts theories on mechanisms of autoimmunity and has translational applications in cancer immunotherapy.