cGAS-STING and therapeutic immune responses in neuroblastoma

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PROJECT SUMMARY AND ABSTRACT The goal of this proposed five-year training program is to foster the development of the applicant's independent research career as a pediatric oncologist focused on exploiting inflammatory sensing pathways to improve immunotherapy in pediatric solid tumors. The candidate has completed a rigorous clinical training course and has a strong research foundation. In the short term, he will benefit from training to obtain research skills to study transcriptional regulation, work with immunocompetent mouse models of neuroblastoma, and analyze the tumor immune microenvironment. His mentors for this award are Dr. Chi Dang, an eminent cancer biologist with expertise in studying transcriptional regulation, and Dr. Michael Hogarty, a world-wide leader in neuroblastoma research. To add broad scientific expertise and provide additional career guidance, he has assembled a Mentoring Committee composed of scientists from diverse and complementary fields. Dr. Wolpaw will benefit from the rich resources and opportunities available at The Children's Hospital of Philadelphia, the University of Pennsylvania, and the Wistar Institute. The proposed research focuses on investigating the regulation of the inflammatory sensing cGAS-STING pathway in neuroblastoma to promote immune-targeting of mesenchymal state neuroblastoma (NBLMES). Neuroblastomas are composed of cells in an adrenergic (NBLADR) state that predominate at diagnosis and a NBLMES state that is initially a minor subpopulation but is a driver of relapse. Dr. Wolpaw's prior work shows that NBLMES cells have higher levels of inflammatory signaling at baseline in vitro and in vivo and are more responsive to some inflammatory stimuli, suggesting a unique immune vulnerability of this critical population. His current proposal capitalizes on these findings by focusing on the clinically relevant inflammatory sensing cGAS-STING pathway. This pathway responds to cytosolic DNA by broadly activating inflammatory signaling and is required for an immunogenic response to radiation therapy, including synergistic and systemic effects when local radiation is combined with immune checkpoint blockade. His preliminary data support the hypothesis that restoration of cGAS-STING will render NBLMES cells vulnerable to immuno-radiation therapy. To test this hypothesis, Dr. Wolpaw will purse two specific aims: 1) Elucidate the impact of NBLADR/NBLMES state on the transcriptional regulation of cGAS-STING and 2) Define the effect of restored cGAS expression on the response to radiation. Together, these aims will advance our understanding of how inflammatory sensors like cGAS-STING are regulated in neuroblastoma and how their manipulation can promote tumor-immune interactions. This will lay the foundation for improved immunotherapies in neuroblastoma and provide the training and experience needed to transition Dr. Wolpaw into an independent physician scientist.