Abstract
Undifferentiated pleomorphic sarcoma (UPS) is one of the most common and aggressive adult soft tissue sarcomas (STS). Once metastatic, UPS is rapidly fatal. Most STS, including UPS, are resistant to conventional immunotherapies as these tumours have low numbers of spontaneous tumour infiltrating lymphocytes (TILs) and are densely populated with immune suppressive macrophages. Intra-tumoural activation of the STimulator of INterferon Genes (STING) pathway is a novel immunotherapeutic strategy to recruit anti-tumour TILs into the tumour microenvironment. In a murine model of UPS, we have demonstrated that intra-tumoural injection of a murine-specific STING agonist, DMXAA, results in profound immune mediated tumour clearance. Recently, molecules capable of activating both human and mouse STING pathways have been developed. In pursuit of clinically relevant therapeutic opportunities, the purpose of this study is to evaluate the anti-tumour potential of two agonists of the human and murine STING receptors: ADU-S100 and MSA-2 as monotherapies and in combination with the immune checkpoint inhibitor, anti-PD1 in a murine model of UPS.
Immune competent mice were engrafted with murine UPS cells in the hindlimb muscle. Once palpable, mice in the monotherapy group were treated with a single intra-tumoural dose of 1) ADU-S100 or 2) MSA-2 or 3) DMXAA. In additional experimental groups, mice were treated with the different STING agonists and monoclonal anti-PD1. Tumour volume measurements and tumour bioluminescence were measured over time. To quantify dynamic changes in immune populations and in the tumour immune microenvironment, STING treated UPS tumours were evaluated using flow cytometry and mRNA quantification at various timepoints after therapy.
DMXAA monotherapy produced complete tumour eradication in 50% of mice, whereas both ADU-S100 or MSA-2 monotherapy only extended survival but did not result in complete tumour clearance. Flow cytometry and transcriptional profiling of tumours at multiple timepoints post-treatment showed similar inflammatory changes and increased TILs numbers across all STING agonists. The addition of anti-PD1 treatment to STING therapy significantly extended survival times with both ADU-S100 and MSA-2, and resulted in 14% complete tumour clearance with ADU-S100. No complete survivors were observed with MSA-2-anti-PD1 combinations therapy.
STING activation is a promising immunotherapeutic strategy for UPS. Recently developed human STING agonists are not as effective as DMXAA despite similar immunologic responses to treatment. STING and anti-PD-1 treatment were therapeutically synergistic for both human STING agonists. These results justify further research around STING activation as a therapeutic modality for STS. DMXAA may possess additional off-target therapeutic properties beyond STING activation which warrants further investigation. Elucidating these differences may be critical to further optimize STING therapy for human STS.
