Haematopoiesis ─ the process by which all blood and immune cells are generated from Haematopoietic Stem and Progenitor Cells (HSPCs) ─ is maintained by the bone marrow (BM) microenvironment, also termed BM niche.
Mesenchymal stromal cells (MSCs) are key elements of the BM niche, tightly controlling HSPC fate and having a role in immunomodulation. In malignancy, these MSCs can act as first sensors of tumor cells and induce a myeloid bias during HSPC differentiation that promotes immunosuppression and tumor support, as proposed based on murine breast cancer studies.
Similarly, neuroblastoma (NB) ─ a paediatric tumor of the sympathetic nervous system─ can metastasize to BM where it interrupts BM homeostasis. This results in anaemia and thrombocytopenia, making blood transfusions common practice during NB therapy.
NB treatment also includes autologous stem cell transplantation (aSCT) and immunotherapy. The immunosuppressive environment in BM3, however, is expected to limit clinical efficacy of immunotherapy as still >40% of the patients experience relapse, most often in BM. In our previous work we observed impaired HSPC mobilisation for aSCT in patients with NB compared to other paediatric tumors and NB-HSPCs showed increased expression of the myeloid marker CD33. Additionally, we found the MSC compartment in NB-infiltrated BM to be dysregulated; showing increased MSC frequency and presence of a CD146-expressing MSC-subtype4 that highly expressed immunosuppressive factors based on single cell RNA sequencing (scRNA-seq). Therefore, we hypothesize that NB-cells hijack normal BM niches in favour of facilitating an immunosuppressive milieu, by instructing MSCs to skew HSPC differentiation as well as modulating MSCs’ immunoregulatory functions.

Overall aim: to unravel how the BM niche ─specifically the MSC compartment─ is hijacked and modified by neuroblastoma tumor cells, to ultimately restore MSC-mediated HSPC support and counteract immunosuppression.