Abstract LB-114: Monogenic autoimmune diseases as a starting point for new immunooncology targets
Authors: Benjamin Schwartz, Kenneth Hance, Johannes Freudenberg, Christopher Shelton, Junping Jing, Jingsong Yang
Journal: Cancer Research (2017)

Abstract Cyclic dinucleotide (CDN) analogs and small molecule agonists of STING (STimulator of INterferon Genes protein) are currently being developed as immuno-oncology agents based on their ability to stimulate potent anti-tumoral responses in the tumor micro-environment (TME) (1,2). STING agonists act primarily on APCs such as dendritic cells (DCs), resulting in enhanced type I interferon signalling and resulting cytotoxic T cell (CTL) responses (3). Germline gain of function mutations in STING (gene name TMEM173) exist and cause the rare disease SAVI (4). Patients with SAVI present as infants with symptoms such as chronic rash, lesions, and systemic inflammation and eventually succumb to more serious complications such as lung disease. At the functional level, they display elevated levels of interferon responsive genes indicative of constitutive STING activation. Thus, while chronic agonism of this pathway leads to an autoimmune/autoinflammatory phenotype, acute dosing has benefit in a tumor setting as an immunological stimulant. We designed an in silico approach to identify other genes with the same potential disease/phenotype profile as STING. We combined knowledge of Mendelian disease genetics with pathway phenotype associations such as involvement in immune cell anergy, activation, costimulation, chemotaxis, and migration. In addition, we determined a putative set of genes associated with immune privileged sites by combining textmining of biomedical literature with mRNA gene expression analysis. Taken together, these approaches provided a list of potential immuno-oncology targets that also included several well-known targets such as CTLA4, ICOS, and OX40 which are either approved or in clinical trials as immuno-oncology agents. This list was then manually curated and prioritized based on literature, and will be functionally validated in ongoing experimental systems. References: 1) Corrales, L., et. al. “Direct Activation of STING in the Tumor Microenvironment Leads to Potent and Systemic Tumor Regression and Immunity” 2015, Cell Reports, v.11, 1018-1030. 2) Chandra, D., et. al. “STING Ligand c-di-GMP Improves Cancer Vaccination against Metastatic Breast Cancer” 2014, Cancer Immunol. Res., v.2(9), 901-910. 3) Woo, S.-R., et. al. “STING-Dependent Cytosolic DNA Sensing Mediates Innate Immune Recognition of Immunogenic Tumors” 2014, Immunity, v.41, 830-842. 4) Liu, Y., et. al. “Activated STING in a Vascular and Pulmonary Syndrome” 2014, N. Engl. J. Med., v.371(6), 507-518. Citation Format: Benjamin Schwartz, Kenneth Hance, Johannes Freudenberg, Christopher Shelton, Junping Jing, Jingsong Yang. Monogenic autoimmune diseases as a starting point for new immunooncology targets [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-114. doi:10.1158/1538-7445.AM2017-LB-114