Background: The tumour microenvironment (TME) plays a critical role in tumour growth, metastasis, and immune response. However, our understanding of the TME in paediatric cancers is limited, hindering the development of effective immunotherapeutic strategies for childhood cancers.
Methods: To address this, we developed novel paediatric cancer models for B-cell acute lymphoblastic leukaemia, acute myeloid leukaemia, group 3 medulloblastoma and embryonal rhabdomyosarcoma, by implanting syngeneic murine cancer cells into infant and adult mice. We characterised host-dependent factors within each TME affecting cancer growth, using a state-of-the-art technique, including single-cell RNA sequencing, spectral flow cytometry, proteomics, and therapeutic response assays.
Results: Tumour growth was found to be 10 times faster in paediatric mice compared to adults, using identical cancer cell lines, suggesting the presence of host-derived, age-specific factors driving increased growth. We identified age-related signatures in childhood cancers. These signatures lower T cell infiltration and cytotoxic CD8+T-cell activation and increased immune suppressive macrophages. Paediatric sarcoma models did not respond to immune checkpoint inhibitors, whereas adult mice, bearing the same sarcoma cells, had a complete response rate of 60-100%.
Conclusion: Our findings provide a deeper understanding of the intricate role of TME in childhood cancer immune response and highlight the importance of considering age-specific factors when developing immunotherapeutic strategies for paediatric cancers. The use of juvenile mouse models for screening drugs that target the TME prior to evaluation in clinical trials may provide an effective strategy to improve outcomes for children with cancer.