Intrinsic STING signaling shapes phagocytosis-dependent innate immunity

About This Grant

ABSTRACT: Our laboratory discovered and confirmed STING (Stimulator of Interferon Genes) as an essential component of the cytosolic DNA-mediated innate immune response pathway. We subsequently demonstrated that STING signaling is commonly suppressed in microbial infected cells or human cancers, which enable such cells to escape the host immunosurveillance system. Our new data, enclosed herein, indicates that intrinsic innate immune STING signaling stimulates the production of essential innate immune proteins that in combination with microbial or self-nucleic acid, renders such cells highly immunogenic. Here, we intend to clarify the mechanisms of how intrinsic STING signaling facilitates the trans-activation of phagocytes and the cross-presentation of microbial or tumor antigen. Aim I: We aim to evaluate the mechanisms by which innate immune STING signaling renders microbial infected cells or DNA-damaged cells immunogenic, compared to normal apoptotic cells (which are non-inflammatory). Our data indicates that cytosolic DNA triggered STING-inducible genes combine with and protect, cytosolic DNA species to enable them to escape DNase-mediated degradation and activate STING signaling, in trans, in engulfing phagocytes. We have now identified these genes and will further characterize their novel mechanisms of action. Aim II. Our data indicates that innate immune STING signaling is suppressed in aged cells by epigenetic silencing. Such cells, for example, STING -/- MEFs or transformed cells lacking cGAS or STING expression, are non- immunogenic following DNA-damaging events, even though they produce cytoplasmic micronuclei. We hypothesize that reconstituting intrinsic STING signaling in vitro and, in vivo, will render cells immunogenic and trigger the innate activation of engulfing phagocytes. We believe that these strategies could shed insight into mechanisms of resistance to cancer therapies, (many of which invoke micronuclei formation) as well as lead to new strategies to help improve the treatment of a wide array of inflammatory and malignant disease.