Profiling cGAS-STING pathway in T-Acute Lymphoblastic Leukemia

Abstract

Abstract Acute lymphoblastic leukemia (ALL) is the most common pediatric malignancy, accounting for over one-quarter of all childhood malignancies. Approximately 15% of ALL derive from the T-cell lineage (T-ALL). Patients with newly diagnosed T-ALL undergo intensive multidrug combination chemotherapy resulting in many side effects. Despite chemotherapy regimens including steroids, and allogeneic transplantation, relapse remains the main challenge in children with T-ALL. Moreover, genetic alterations have been extensively examined in recent years; however, there are still currently few prognostic markers for therapy response. Therefore, alternative treatments are needed to treat this disease and improve overall survival. The cyclic GMP-AMP synthase - Stimulator of Interferon Genes (cGAS-STING) pathway has emerged as a possible target in treatment of cancers, aiming to increase anti-tumor immunity. Most clinical trials to-date have focused on STING agonists used for solid tumors. Interestingly, the high activation of this pathway in normal T cells can lead to ER stress and cell death via the activation of the BH3-family. The status of cGAS-STING pathway in T-ALL is largely unknown. We hypothesize that the cGAS-STING pathway is defective in T-ALL, thus protecting these malignant cells from apoptosis, and that increasing cGAS-STING activity may be a way of enhancing the treatment of this disease. Our preliminary data shows that some T-ALL cell lines do not produce IFN-β after stimulation to STING agonist. Also, some of these cell lines have a decreased cGAS expression, and have a decreased rate of apoptosis compared to healthy T-cells. Our project will hopefully lay the foundation for future targeted immunotherapies for treating T-ALL. Center for Pediatric Immunotherapy at Rainbow