Innate immune sensing in the tumor microenvironment (TME) is a critical step in promoting spontaneous tumor-initiated T cell priming and subsequent tumor-infiltrating lymphocytes (TILs) infiltration. Spontaneous tumor-initiated T cell priming is dependent on IFN-β production by tumor-resident dendritic cells. In particular, activating STING induces the signature cytokine IFN-β. Activation of the STING pathway in tumor-resident host antigen presenting cells (APCs) is required for induction of a spontaneous CD8+ T cell response against tumor-derived antigens in vivo. Bacterial infection produces exogenous cyclic dinucleotides (CDNs), and host cyclic GMP-AMP synthetase (cGAS) produces a structurally distinct endogenous cyclic dinucleotide. In this study, Leticia Corrales, et al selected ADU-S100 (ML RR-S2 CDA) as the lead molecule for continued development. Especially, ADU-S100 is a strong agonist of the mSTING pathway in vitro and in vivo.

ADU-S100 has high translational potential as a therapeutic intervention strategy to induce activation of the tumor microenvironment in multiple tumor types. Particularly, ADU-S100 has the mechanistic goal of generating effective tumor-initiated CD8+ T cell priming and lasting antitumor efficacy. ADU-S100 also induces aggregation of STING and induce phosphorylation of TBK1 and IRF3 in mouse bone marrow-derived macrophages (BMM). Besides, ADU-S100 induces significantly high levels of IFN-α. Importantly, ADU-S100 also shows high anti-tumor control than the endogenous ML cGAMP. ML RR-S2 CDA induces lasting immune-mediated tumor rejection in multiple tumor types. Together, ADU-S100 promotes immune-mediated tumor rejection.

All in all, these results demonstrate that ADU-S100 eradicates multiple tumor types and primes an effective systemic CD8+ T cell immune response that significantly inhibits the growth of distal, untreated lesions.

Corrales L, et al. Direct Activation of STING in the Tumor Microenvironment Leads to Potent and Systemic Tumor Regression and Immunity. Cell Rep. 2015 May 19;11(7):1018-30.