DNA sensing via STING regulates immune responses in a lung cancer model via IDO

Abstract

Abstract The Stimulator of Interferon Genes (STING) is a signaling adaptor associated with the endoplasmic reticulum. STING is activated by cytosolic DNA sensors to stimulate IFN type I expression (IFN-I). Recent reports revealed that DNA sensing to activate STING in dendritic cells (DCs) that engulfed dying tumor cells impeded growth of immunogenic tumors and potentiated responses to therapy. Consistent with these findings, synthetic STING agonists enhanced tumor regression. Paradoxically, Lewis Lung Carcinoma (LLC) grew slower in STING-deficient mice, revealing that STING is required for optimal LLC growth. Mechanistically, STING ablation abolished upregulation of the immunoregulatory enzyme, indoleamine 2,3 dioxygenase (IDO) in DCs located in tumor draining lymph nodes during LLC growth. Also, expression of the regulatory cytokine IL-10 and infiltration of myeloid derived suppressor cells (MDSCs) into the tumor microenvironment (TME) was diminished in mice lacking STING. In contrast, STING was not required for optimal growth of LLC tumors expressing neo-antigens, revealing a pivotal role for tumor antigenicity in influencing responses to DNA in the TME. These findings support the hypothesis that DNA from dying cells are sensed in the TME to activate STING, which induces dominant regulatory responses via IDO when tumor antigenicity is low and dominant immunogenic responses when tumor antigenicity is enhanced. Thus, cytosolic DNA sensing to activate STING has dichotomous roles in the TME, and tumor antigenicity is a pivotal factor influencing immune responses to DNA at sites of chronic inflammation associated with tumor growth.