IGF2BP1 fosters an immunosuppressive tumor microenvironment in high-risk neuroblastoma, contributing to their resistance to immunotherapy.

ABSTRACT: Incorporation of the current immunotherapy, GD2-targeting monoclonal antibody into the standard of care has moderately improved clinical outcomes in children with high-risk neuroblastoma (HR-NB), however, the overall survival remains low. More than 50% of patients with HR-NBs are refractory to or eventually develop resistance towards anti-GD2 treatment. HR-NBs in general are known to exhibit low tumor-mutational burden, are immunologically cold and possess an immunosuppressive tumor microenvironment. Understanding the mechanisms of immune evasion may provide novel targets for improving the efficacy of immunotherapies for these immunologically cold HR-NBs. Here, utilizing immunocompetent mouse models of immunologically cold HR-NB, we uncovered a novel function of IGF2BP1 in promoting immune escape of neuroblastoma tumors. We demonstrate that neuroblastoma cell-specific knockdown of IGF2BP1 favorably alters the tumor microenvironment of HR-NBs, turning these “immunologically cold” tumors to an immunogenic type, thereby priming them for anti-GD2 therapy-induced immune responses. Downregulation of IGF2BP1 in NB cells decreased the immunosuppressive T-regulatory and dysfunctional/exhausted CD8 T cells; and promoted the accumulation of effector MHCII+ macrophages at the tumor site. Importantly, knockdown of IGF2BP1 along with anti-GD2 immunotherapy induced a synergistic immunogenic effect and achieved a potent anti-tumor response in HR-NB mouse model, with increased accumulation of effector CD8+ T cells and CD86+ macrophages, but decreased MDSCs in the tumor microenvironment. Thus, disrupting NB cancer cell IGF2BP1-mediated immunosuppression is a potential approach for improving the efficacy of anti-GD2 immunotherapy towards HR-NBs.

ORGANISM(S): Mus musculus

PROVIDER: GSE336887 | GEO | 2026/06/30

REPOSITORIES: GEO