PROJECT SUMMARY Neuroblastoma (NB) is the most common extracranial solid tumor of childhood that leads to a disproportionate number of childhood cancer deaths and an even more disproportionate death rate in Black children. Despite the addition of GD2 antibody (dinutuximab) immunotherapy, disparities in outcome remain, suggesting racial/ethnic differences in immunity may contribute to NB patient health inequity. While social determinants of health (SDOH) like household poverty have been found to play a role in outcome disparities for high risk NB, biologic factors contributing to racial disparities in NB survival are largely unexplored. Dinutuximab requires innate effector immune cells to enact antibody dependent cellular cytotoxicity (ADCC) for efficacy. We have found that the presence of circulating cytotoxic natural killer (NK) cells is associated with objective responses to dinutuximab in a phase I trial for patients with relapsed NB. Furthermore, innate immune cell infiltrates in high-risk NB tumors may differ between Black and non-Hispanic White patients, with Black patients having more exhausted tumor-resident NK cells. We therefore hypothesize that racial differences in high-risk NB patient innate immune cell landscapes, due to genomic ancestry and SDOH exposures, contribute to outcome disparities following GD2 immunotherapy. A Children’s Oncology Group randomized phase III trial will evaluate whether the addition of dinutuximab to induction chemotherapy (“induction chemoimmunotherapy”) will improve event-free survival (EFS) and overall survival (OS) for newly diagnosed high-risk NB patients. The trial includes a novel embedded health equity substudy to capture parent-reported race and SDOH. The goal of this proposal is to utilize trial-derived biologic samples to: i) Perform tumor based single cell genomic, proteomic, and functional investigations before and after chemoimmunotherapy to determine tumor immune microenvironment markers influencing EFS/OS, ii) Perform immunophenotyping and functional assays to define peripheral host immune markers influencing EFS/OS, and iii) Explore the associations between tumor and host immune landscapes and parent-reported race, adverse SDOH, child DNA-based genetic ancestry, and clinical outcomes. At the conclusion of this project, we will have defined immune biomarkers of EFS/OS across all patients and evaluated immune biomarkers of poor EFS/OS to see if they are enriched in Black children and/or children exposed to adverse SDOH. Importantly, these findings may identify new immunotherapeutic targets for specific patient populations to improve survival and achieve health equity in patients with high-risk neuroblastoma.