Research on pathophysiology and therapeutic development from the perspective of the tumor microenvironment in neuroblastoma by pediatric surgeons

Abstract

[Introduction] The tumor microenvironment (TME) plays a central role in metastasis and therapeutic resistance in neuroblastoma. From a pediatric surgical perspective, this study presents three lines of basic research targeting the TME in neuroblastoma.

[Development of GD2-targeted MSC-based immunotherapy] Focusing on mesenchymal stem cells (MSCs), we first demonstrated their tumor-homing capacity in MYCN transgenic mice (TgM). IFN-β–expressing MSCs exhibited significant antitumor effects. Building on these findings, MSCs were engineered to express anti-GD2 antibodies. These cells demonstrated antibody-dependent cellular cytotoxicity (ADCC) against neuroblastoma cell lines in vitro and suppressed tumor growth in vivo. A bone marrow metastasis model is currently under development to further assess therapeutic efficacy.

[Effect of MEK inhibition in a minimal residual disease (MRD) model] Using the MEK inhibitor trametinib, short-term tumor growth suppression was confirmed in a neuroblastoma xenograft model. A postoperative MRD model was subsequently established following tumor resection, demonstrating that trametinib inhibited tumor recurrence and prolonged survival, indicating its potential role in relapse prevention.

[Impact of surgical stress on metastatic progression] In a syngeneic subcutaneous model using MYCN TgM-derived tumor cells, spontaneous distant metastasis was observed during tumor progression, with enhanced metastatic growth following primary tumor resection. Further analysis indicated that surgical manipulation and systemic inflammatory responses, including IL-6 elevation, may contribute to accelerated metastasis.

[Conclusion] Through immunotherapy development, surgically derived mouse models, and investigation of surgical stress, this work advances TME-focused neuroblastoma research toward clinical translation.