Mesenchymal transition as a potential mechanism of late immune evasion in neuroblastoma: a case of late relapse after allogeneic hematopoietic stem cell transplantation

Neuroblastoma is the most common extracranial solid malignant tumor in children, and relapse remains a major challenge in high-risk disease. Immune escape and phenotypic plasticity have been implicated in treatment resistance. Neuroblastoma cells can exist along adrenergic and mesenchymal transcriptional states; mesenchymal-like cells have been associated with increased therapy resistance and migratory capacity. Here, we describe a child with high-risk neuroblastoma who experienced late relapse after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Flow cytometry of recurrent bone marrow tumor cells showed an immunophenotype compatible with a mesenchymal-like state. By integrating the clinical course and available molecular data, we discuss phenotypic plasticity as a possible contributor to late immune escape and relapse after allo-HSCT. We present a patient with stage M neuroblastoma who achieved complete remission after surgery, chemotherapy, radiotherapy, and allogeneic hematopoietic stem cell transplantation, but experienced bone and bone marrow relapse three years post-transplantation. Flow cytometry of the bone marrow revealed mesenchymal transition in the tumor cells. The case harbored multiple gene mutations associated with poor prognosis in neuroblastoma. Following relapse, the patient has received two cycles of chemotherapy and achieved partial response. In this single case, mesenchymal-like immunophenotypic features in recurrent neuroblastoma cells may have contributed to late relapse and immune escape after allo-HSCT. A high-risk genetic background, treatment-related factors, lack of radiotherapy to eventual relapse sites, and the absence of post-transplant anti-GD2 immunotherapy may also have contributed to disease recurrence. Because paired diagnostic and relapse samples were not available for the same phenotypic analyses, these findings should be interpreted as hypothesis-generating and require validation in longitudinal cohorts and functional models. The treatment protocol for this patient was conducted under the clinical trial registered at ClinicalTrials.gov (Identifier: NCT05303727, First submitted :March 16, 2022).