HICCC Interdisciplinary Research Seminar
Eileen Connolly, MD, PhD, Assistant Professor of Radiation Oncology, Member, HICCC Tumor Biology & Microenvironment Program and HICCC Velocity Fellow (left) and Darrell Yamashiro, MD, Professor of Pediatrics and of Pathology and Cell Biology, Member, HICCC Precision Oncology and Systems Biology Program
Inhibition of Notch synergizes with Checkpoint Inhibition and High-dose Radiation
High-dose radiation therapy (HDRT), clinically delivered as Stereotactic Body Radiation Therapy (SBRT), has a profound immunostimulatory effect on tumors and is frequently combined with immunotherapy. Our group and others have shown that HDRT, can also induce an immunosuppressive response, by attracting regulatory T-cells (Treg), and tissue-associated macrophages (TAM), to the tumor microenvironment (TME). There is a lack of understanding of how HDRT interacts with different components of the TME. This talk will focus on our work evaluating the response of endothelial cells (ECs) and the Notch signaling pathway (which is implicated in both EC and immune cell function) to HDRT in a murine model of neuroblastoma. We will discuss our recent data demonstrating that combining Notch inhibition, using a γ-secretase inhibitor (GSI), with anti-PD1 therapy and HDRT, results in a synergistic and durable tumor growth inhibition and outline our translational efforts to bring these insights to the clinic to improve outcomes for our patients.