ID #615 An integrated hla and neoepitope atlas of paediatric cancer models enables neoantigen-targeted immunotherapy development

Abstract

Paediatric cancers are the leading cause of disease-related mortality in children, with approximately 400,000 diagnoses annually worldwide. Central nervous system (CNS) tumours are the most common childhood solid malignancies and account for the highest proportion of cancer-related deaths. Cancer immunotherapy offers a potentially less toxic treatment option for paediatric patients, with tumour-derived neoepitopes presented by human leukocyte antigen (HLA) class I molecules emerging as promising targets. However, HLA downregulation and poor antigen presentation limit anti-tumour immune responses in paediatric CNS tumours. A detailed understanding of antigen processing and presentation is critical for advancing next-generation precision immunotherapies in paediatric oncology.

Using the Childhood Cancer Model Atlas (CCMA), we curated a catalogue of class I HLA types and neoepitopes across 287 cell line models, with a focus on CNS tumours (177 models). HLA-A, B, and C types were inferred at four-digit resolution from sequencing data and curated to assess allele diversity, balance, and expression. Interestingly, we observed homozygosity across all three HLA class I loci in several models. HLA allele-specific expression loss was also commonly detected across paediatric cancer types, consistent with tumour immune evasion. To further characterise the immunogenic potential of CCMA models, neoepitopes were predicted by integrating somatic variants with matched HLA types and prioritised using binding affinity and elution likelihood. From this refined set of high-confidence candidates, we identified neoepitopes derived from recurrent driver mutations and observed overlap with experimentally validated epitopes from the Immune Epitope Database. Collectively, our analysis reveals significant HLA allele-specific downregulation in CNS tumours and other paediatric cancers. Integration of HLA genotype, expression, and the predicted neoepitope repertoire provides a foundation for neoantigen-based immunotherapy development. We believe the CCMA dataset will serve as a valuable public resource and enable a broader range of research for the treatment of paediatric cancer.