Investigating the Stimulator of Interferon Genes Pathway as a Translational Immunogenic Therapy for Soft Tissue Sarcoma
Date
2024-06-17
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Abstract
Undifferentiated pleomorphic sarcoma (UPS) is one of the most common, aggressive, and metastatic soft tissue sarcomas in adults. Generally, UPS are unresponsive to conventional chemotherapies or immunotherapies, which is believed to be attributed to the immunosuppressive tumor microenvironment (TME) of these malignancies. Preclinical studies in the murine KP model of UPS showed that intratumoral (i.t.) activation of the STimulator of INterferon Genes (STING) pathway using the murine STING agonist DMXAA, elicited immune mediated UPS clearance in 50-75% of treated mice. To assess the translational potential of STING immunotherapy, I tested the anti-tumor efficacy of three STING agonists in the KP model of UPS capable of activating both human and murine STING. Excitingly, E7766 emerged as a translational STING agonist which can shift the UPS TME towards an immunologically inflamed phenotype. Thirty-eight percent of E7766 treated mice eradicated their primary tumors which was CD8+ T-cell dependent. Of the mice that eradicated primary UPS tumors, 87.5% develop protective immunity against UPS re-challenge. Next, I investigated which cell types in the UPS TME engage in STING signaling following therapy. I found that STING expression in non-malignant host cells and not UPS cells is required to observe tumor eradication following STING immunotherapy. Single cell RNA sequencing of UPS tumors revealed that neutrophils are abundant cells in the TMEs of UPS tumors treated with DMXAA and E7766 at both timepoints. Myeloid cells were identified as the cell type with the highest interferon stimulated gene (ISG) score. Both DMXAA and E7766 maintain higher ISG scores in myeloid and lymphoid cells relative to control and CDN at the 1-week timepoint. Finally, I developed a novel gene therapy tool to explore forced expression of the constitutively active mutant hSTINGN154S protein using plasmid DNA. Using these tools, I transfected TAO1 UPS and HEK293T cells and confirmed the functional status of the hSTINGN154S protein’s expression in vitro. In summary, these data suggest that E7766 is an exciting therapeutic candidate for UPS, and further investigation into the importance and consequences of STING signaling in various UPS TME cell types is required to understand therapeutic mechanisms of this therapy.
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Keywords
Stimulator of interferon genes, Undifferentiated pleomorphic sarcoma, Soft tissue sarcoma, Immunotherapy, Tumor microenvironment
Citation
Hildebrand, K. M. (2024). Investigating the stimulator of interferon genes pathway as a translational immunogenic therapy for soft tissue sarcoma (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca.