Abstract 2277: Assessment of the response to STING agonist treatment and potentiation by manganese in glioblastoma cells and the tumor microenvironment
Authors: Schmidt Andrea , Sweeney Caroline , Hawkins William M. , Jimenez-Macias Jorge L. , Lawler Sean 
Published: April 2023

Abstract
Glioblastoma (GBM) is the most common form of primary malignant brain tumor. Current treatment consists of tumor resection followed by chemoradiotherapy which yields a 5-year survival rate of only 6.8%. The average survival for newly diagnosed patients is only 14-15 months, highlighting the need for improved therapies. The tumor microenvironment (TME) of GBM is highly immunosuppressive, preventing successful treatment by immunotherapies like immune checkpoint blockade. Our lab is interested in identifying potential targets in GBM that would allow for increased immune infiltration in the tumor microenvironment, thus enhancing the efficacy of immunotherapies. Stimulator of interferon genes (STING) plays a central role in innate pathogen sensing and has been implicated in cancer as a potential immunostimulatory therapeutic target. Our previous work demonstrated the functionality of the STING pathway in GBM mouse models and patient samples. We have also shown increased infiltration of innate immune cells in the TME and significant survival benefits after treatment with the STING agonist ADU-S-100 in GL261 and CT-2A mouse models. In vitro studies in cultured GBM cell lines and normal cells found in the GBM TME such as human cerebral microvascular endothelial cells (HCMECs) in the presence of ADU-S100 showed a robust type I IFN response in endothelial cells but not in tumor cells. Western blotting showed the presence of all the major STING signaling pathway components in GBM cells, raising the question of how the STING pathway is regulated in tumor cells. To investigate this further we have performed cytokine profiling of GBM cells and HCMECs upon treatment with ADU-S100. This confirmed a strong Type I interferon response in HCMECs, and a distinct response in GBM cells, showing that tumor cells respond to STING activity via alterations in cytokine secretion, but in a different way from TME cells. Finally, manganese has been highlighted as a possible potentiator of STING agonist activity in other cancer types. Combination of manganese with ADU-S100 showed enhanced protein expression of downstream STING pathway components in HCMECs as well as in GBM cells through Western blot. Furthermore, manganese alters the cytokine profile in combination with ADU-S100 relative to untreated or ADU-S100 alone suggesting enhancement of immune signaling. Taken together, these results suggest potentiation of ADU-S100 by manganese in GBM. In conclusion, STING agonists are promising agents for local immunostimulation in GBM, and their activity may be enhanced by combination with manganese. Ongoing experiments are aimed at elucidating mechanistic insights into these concepts.
Citation Format: Andrea Schmidt, Caroline Sweeney, William M. Hawkins, Jorge L. Jimenez-Macias, Sean Lawler. Assessment of the response to STING agonist treatment and potentiation by manganese in glioblastoma cells and the tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2277.