Antagonism of regulatory ISGs enhances the anti-melanoma efficacy of STING agonists

Abstract

Abstract STimulator of INterferon Genes (STING) is a dsDNA sensor that triggers type I inflammatory responses. Recently this pathway has been leveraged as a cancer treatment with the use of STING agonists. Our lab has previously demonstrated that treating mice bearing established tumors with STING agonists leads to an inhibition in tumor growth in association with tumor vascular normalization and immune cell recruitment within the tumor microenvironment. However, STING agonism also results in the upregulated expression of regulatory interferon-stimulated genes (ISGs), including ARG2, enzymes involved in the production of immunosuppressive prostaglandins (i.e., PTGES and PTGS2/COX2), PD-L1, and ISG15, which limit the overall efficacy of this immunotherapeutic paradigm. We hypothesized that combined treatment of melanoma-bearing mice with STING agonists along with targeted inhibitors of ARG2, PTGES/COX2, PD-L1, and ISG15 would result in improved control of tumor growth and more robust anti-tumor immune responses in vivo.In the B16 (BRAF WTPTEN WT) melanoma model, we observed improvement in tumor growth control after treatment with STING agonists + blocking anti-PD-L1 or anti-ISG15 antibodies vs. monotherapy. However, in the BPR (BRAF V600EPTEN −/−) melanoma model, tumor growth control over that observed for STING agonist alone was only noted upon combined addition of pharmacologic inhibitors of ARG2, COX2, and NOS2. The underlying therapy-associated changes in the TIME that support improved tumor growth control are currently being evaluated by single cell RNAseq, flow cytometry, and IFM to discern mechanism(s) of action. Supported by grants from NIH (P01 CA234212) and the AAI Careers in Immunology Fellowship.