Js07.6.a Age-Appropriate Models of Paediatric Brain Tumours Reveal the Influence of Age on Tumour-Immune Interaction.

BACKGROUND The developing immune system of a child is distinct to that of an adult. These differences in the immune system are often ignored in preclinical paediatric cancer research, where adult mice are more commonly used, overlooking potential developmental influences on cancer-microenvironment interactions. These influences are of particular importance when testing immunotherapeutic agents for paediatric cancers. MATERIAL AND METHODS Here, we sought to understand the impact of age on brain tumour progression and tumour-immune interactions. To address this, we have developed paediatric brain cancer mouse models which reflect the developing microenvironment in which these tumours arise. Using spectral flow cytometry, RNA sequencing, and immunohistochemistry, we have characterised differences in the tumour-immune microenvironment of multiple orthotopically-implanted murine brain tumour models in juvenile mice compared to adults. RESULTS We found that identical brain tumour cells elicited tumours that grew faster in juvenile mice and had reduced immune cell infiltration compared to adults. Moreover, immune infiltrates were markedly distinct between juvenile and adult mice. Specifically, juvenile mice possessed more naïve-like CD8 T cells and reduced effector, resident, and exhausted-like CD8 T cells. Tumour-associated macrophages in juvenile mice had reduced MHC II expression and appeared polarized towards an anti-inflammatory state, potentially suppressing effective anti-tumour immune responses. Importantly, we demonstrate that repolarisation of macrophages using immune-modulating agents changed the paediatric tumour-infiltrating immune microenvironment towards a more “adult-like state”, that may enhance immunotherapy effectiveness. CONCLUSION Our findings highlight the significant influence of preclinical model age on cancer-microenvironment interactions. Acknowledging the challenge in finding an appropriate match for human development in mice, these data strongly support the use of age-relevant models in preclinical paediatric cancer studies, especially when evaluating agents which target the microenvironment.