Tumor and host immune signatures associated with patient outcomes to GD2 chemoimmunotherapy in neuroblastoma

Neuroblastoma, the most common extracranial solid malignancy in children, continues to have poor long-term survival (~50%) among high‑risk patients, despite the addition of monoclonal anti‑GD2 antibody therapy. Recent studies suggest that variability in immune cell function, such as the presence and activity of innate effector cells (NK cells), may influence antibody therapy outcomes. Differences in tumor-infiltrating immune cells and peripheral immune cell functionality are also emerging as important contributors to immunotherapy effectiveness. This project will integrate tumor and host immune profiling—including single‑cell genomics, proteomics, mass cytometry, and ex vivo functional assays—using biospecimens from the Children’s Oncology Group (COG) ANBL2131 Phase III trial to identify biomarkers of response or resistance to GD2‑directed chemoimmunotherapy given to newly diagnosed high risk neuroblastoma patients. Aim 1 will characterize tumor immune microenvironments pre‑ and post‑treatment to define tumor immune landscapes associated with outcome. Aim 2 will assess functional capacity and phenotypes of circulating effector cells to determine their role in antibody‑dependent cytotoxicity and survival. Aim 3 will correlate immune states with inherited germline variation and early life exposure data to determine factors shaping patient immune fitness and therapeutic response. Together, this approach aims to elucidate mechanisms underlying variability in immunotherapy outcomes and enable the development of more effective, tailored treatment strategies that improve high risk neuroblastoma patient survival and reduce toxicity.