The role of STING agonist-induced interferon stimulated genes in the anti-melanoma immune response

Successful infiltration of pro-inflammatory immune cells into the tumor can promote an anti-tumor microenvironment that leads to tumor growth control and regression. However, the tumor has many mechanisms, both intrinsic and extrinsic, to inhibit the anti-tumor immune response and promote a pro-tumor microenvironment. Recently, treatment of solid tumors with STING agonists has been investigated pre-clinically and clinically as a strategy to promote immune cell entry into the tumor and exert their anti-tumor effector function in the tumor, which can be exploited for cancer immunotherapies. STING is a cytosolic dsDNA sensor that induces the expression of type I interferons and other interferon stimulated genes upon its activation, leading to immune cell entry into the tumor and a delay in tumor growth. Although many STING agonists have shown promise in pre-clinical and early phase clinical testing, they have been unable to induce complete tumor regressions. One reason for this result is the upregulation of inhibitory molecules in the tumor following treatment with STING agonists. In this thesis, I show that treatment of murine melanoma with antagonists of these inhibitory molecules (ARG2, COX2, NOS2, ISG15, PD-L1) in combination with STING agonist, ADU-S100, leads to an improvement in tumor growth control compared to STING agonist monotherapy. In the B16 melanoma model, the combination of anti-PD-L1 + ADU-S100 or anti-ISG15 + ADU-S100 leads to a delay in tumor growth compared to ADU-S100 alone. This therapeutic response is driven by changes in the myeloid and lymphoid compartments that promote an inflammatory, anti-tumor microenvironment. Meanwhile, in the BPR20 melanoma model, treatment with ARG2i/COX2i/NOS2i + ADU-S100 promotes improved tumor growth control compared to ADU- S100 alone. These changes in tumor growth are associated with the increased expression of genes associated with inflammation and an anti-tumor immune response and the decreased expression of genes associated with tumor growth and survival. Overall, these data demonstrate that tumor- mediated mechanisms of resistance to therapy can be overcome and provide guidance for future combination therapies.