STING agonism combined with arginase and PTGES/COX2 inhibitors for improved anti -tumor immunotherapeutic benefit

Abstract Tertiary lymphoid structures (TLS) are non-encapsulated immune cell aggregates that form at sites of chronic inflammation. Recent studies have shown that the presence of TLS in human tumors predicts extended survival and superior response to interventional immunotherapy. Our lab has recently demonstrated that treating mice bearing established tumors with agonists of STING, a cytosolic dsDNA sensor, leads to an inhibition in tumor growth in association with tumor vascular normalization, immune cell recruitment, and local formation of non-classical TLS within the tumor microenvironment. However, STING agonism also results in the upregulated expression of compensatory immune regulatory molecules, including ARG2 and enzymes involved in the production of immunosuppressive prostaglandins (i.e. PTGES and PTGS2/COX2), yielding an overall sub-optimal therapeutic paradigm. We are currently determining if combined treatment with STING agonists along with pharmacologic inhibitors of ARG2 and/or PTGES/COX2 results in improved control of tumor growth, increased formation of TLS, and more robust anti-tumor immune responses in vivo in murine melanoma models.