MODL-05. Age-appropriate models of pediatric brain tumors reveal age-dependent tumor-immune interactions.

Abstract The developing immune system of a child is distinct to that of an adult. These immunological differences are often ignored in preclinical pediatric cancer research, where adult mice are more commonly used, potentially overlooking developmental influences on cancer-microenvironment interactions. This is of particular importance when testing immunotherapeutic agents for pediatric cancers. To address this issue, we have developed pediatric brain cancer mouse models which reflect the developing microenvironment in which these tumors arise. By doing so, we sought to understand the impact of age on tumor progression and immune interactions. Using flow cytometry, RNA sequencing, and immunohistochemistry, we have characterized differences in the tumor-immune microenvironment of multiple orthotopically-implanted murine brain tumor models in juvenile mice compared to adults. We found that identical brain tumor cells elicited tumors that grew faster in juvenile mice and had fewer immune cell infiltrates. Moreover, these immune infiltrates were markedly distinct between juvenile and adult mice. Specifically, juvenile mice possessed more naïve-like CD8 T cells with reduced effector, resident, and exhausted-like CD8 T cells. Tumor-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 repolarization of macrophages using immune-modulating agents changed the pediatric tumor-infiltrating immune microenvironment towards a more “adult-like state”, that may enhance immunotherapy effectiveness. Acknowledging the challenges in finding an appropriate match for human developmental stage in mice, our findings highlight that preclinical model age significantly influences cancer-immune interactions. These data strongly support the use of age-relevant models in preclinical pediatric cancer studies, especially when evaluating microenvironment-targeting agents.