Dhamdhere Mayura R, Gowda Chethana P, Imamura Yuka, Wang Hong-Gang, Schell Todd S, Spiegelman Vladimir S
Division of Pediatric Hematology and Oncology, Department of Pediatrics, The Pennsylvania State University College of Medicine, Hershey, PA, USA.
Department of Neuroscience & Experimental Therapeutics, The Pennsylvania State University University College of Medicine, Hershey, PA, USA.
Oncoimmunology. 2025 Dec 31;14(1):2584408. doi: 10.1080/2162402X.2025.2584408. Epub 2025 Dec 2.
The incorporation of the current immunotherapy, GD2-targeting monoclonal antibodies, into the standard of care has moderately improved clinical outcomes in children with high-risk neuroblastoma (HR-NB); however, overall survival remains low. More than 50% of patients with HR-NB are refractory to or eventually develop resistance to anti-GD2 treatment. HR-NBs are generally known to have a 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 revealed a novel function of IGF2BP1 in promoting the 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 into an immunogenic type, thereby priming them for anti-GD2 therapy-induced immune responses. Downregulation of IGF2BP1 in NB cells decreased the number of 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 antitumor response in an HR-NB mouse model, with increased accumulation of effector CD8+ T cells and CD86+ macrophages but decreased MDSC numbers 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.
将目前的免疫疗法——靶向GD2的单克隆抗体纳入标准治疗方案后，高危神经母细胞瘤（HR-NB）患儿的临床结局有了适度改善；然而，总体生存率仍然较低。超过50%的HR-NB患者对抗GD2治疗难治或最终产生耐药性。HR-NB通常已知具有低肿瘤突变负担，免疫原性低且拥有免疫抑制性肿瘤微环境。了解免疫逃逸机制可能为提高这些免疫原性低的HR-NB免疫疗法的疗效提供新的靶点。在此，利用免疫原性低的HR-NB的免疫活性小鼠模型，我们揭示了IGF2BP1在促进神经母细胞瘤肿瘤免疫逃逸中的新功能。我们证明，神经母细胞瘤细胞特异性敲低IGF2BP1可有利地改变HR-NB的肿瘤微环境，将这些“免疫原性低”的肿瘤转变为免疫原性类型，从而使其对抗GD2治疗诱导的免疫反应致敏。NB细胞中IGF2BP1的下调减少了免疫抑制性调节性T细胞和功能失调/耗竭的CD8+T细胞的数量，并促进了效应性MHCII+巨噬细胞在肿瘤部位的积累。重要的是，在HR-NB小鼠模型中，敲低IGF2BP1并联合抗GD2免疫疗法可诱导协同免疫原性效应并实现有效的抗肿瘤反应，肿瘤微环境中效应性CD8+T细胞和CD86+巨噬细胞的积累增加，但MDSC数量减少。因此，破坏NB癌细胞IGF2BP1介导的免疫抑制是提高抗GD2免疫疗法对HR-NB疗效的一种潜在方法。
