Unveiling the temporal impact: Exploring dynamic changes in the paediatric solid tumour immune microenvironment through time

Abstract

The composition of the tumour immune microenvironment (TIME) influences tumour evolution and responsiveness to immunotherapy. While longitudinal changes in TIME have been well-characterized in adult cancers, its dynamics in childhood cancers remain poorly documented, limiting our ability to predict treatment responses and tailor immunotherapeutic strategies. This study aimed to evaluate the plasticity of TIME in paediatric solid tumours, investigate its longitudinal evolution, and identify time-dependent immune alterations. Transcriptomic data from longitudinal samples of 27 paediatric patients (<21 years old) with relapsed or refractory solid tumours were analysed, encompassing 70 timepoints: 16 diagnoses and 54 successive relapses. TIME plasticity was assessed using gene expression clustering and immune cell infiltration enumeration. Patient-adjusted longitudinal analyses were performed using generalised linear mixed models (glmmSeq), adjusted for age and sex. Temporal associations of immune changes were further explored using dynamic regression models. Thirteen patients exhibited significant changes in their TIME profile, indicating high TIME plasticity. Over time, the TIME shifted toward a tolerogenic and immunosuppressive state, characterised by decreased activity in immune pathways (e.g., T cell receptor signalling) and enrichment of tolerogenic (e.g., macrophage differentiation) and oncogenic pathways (e.g., IL6-JAK-STAT3). The core enrichment of upregulated pathways contained key immunosuppressive factors: immune checkpoints (CTLA-4), tumour-associated macrophage activators (CSF1/CSF1R), T-regulatory cell activators (TGFB1), and immunosuppressive genes (IL10RA). This study provides evidence that the TIME in paediatric solid tumours is plastic and remodels towards immune depletion and tolerogenicity. This evolution may underlie treatment resistance and disease progression, underscoring the need for TIME-informed therapeutic approaches in paediatric oncology. Significance StatementThis article demonstrates the plasticity of the tumour immune micro-environment (TIME) of paediatric solid tumours throughout disease evolution. Longitudinal transcriptomic analyses of 70 tumour samples from 27 patients showed a progressive remodelling towards tolerogenicity and immune depletion. Key immunosuppressive factors, including immune checkpoints and tumour-associated macrophages, were identified as potential contributors to immune escape. These findings support the relevance of longitudinal immune monitoring in paediatric oncology and may inform future strategies for immunotherapeutic interventions.