189 Genomic landscape and systemic immune states across pediatric solid tumors

Abstract

<h3>Background</h3> Childhood cancer is the second most common cause of death among children in developed countries, although the field of cancer immunotherapy has advanced dramatically, children with solid tumors have not benefitted much from these advances. Pediatric cancers have traditionally been considered non-immunogenic due to their lower mutational burden. However, with more pediatric tumors recently sequenced, it has become apparent that there are considerable variations in the mutational load burden (TMB) among tumors from pediatric patients. So better knowledge of pediatric cancer genomics as well as immunology is needed to advance this field further. <h3>Methods</h3> Whole genome analysis was performed on 140 samples obtained from 135 patients, covering 22 types of childhood solid tumors from Karolinska Hospital. Sarek pipelines were then used to call variants for downstream analysis. Mutational signatures, which are characteristic patterns of somatic mutations reflecting the underlying mutational processes, were extracted using the SigProfiler tool. Immune cell compositions and plasma proteins were measured by mass cytometry (CyTOF) and Olink. Additionally, bulk RNA-seq data from tumor tissues were used to estimate immune cell infiltration and TCR expansion. <h3>Results</h3> Compared with adult patients from TCGA, pediatric cancer exhibits a comparatively lower tumor mutational burden (TMB). However, TMB escalates after relapse or metastasis. Furthermore, the ISAC cohort analysis revealed distinct TMB patterns across different pediatric cancers. It is noteworthy that all samples in the ISAC cohort are microsatellite stable. In-depth analysis identified a total of 38 Single Base Substitution (SBS) signatures and 10 Insertion-Deletion (ID) signatures. ID and SBS signatures with similar etiologies are strongly correlated. SBS40, whose etiology is unknown, is highly associated with high mutation rates, in contrast to the notably low TMB in the APOBEC signature. The TMB-high group shows stronger Th1 responses. For Neuroblastoma (NB), a clear demarcation exists between groups with high and low TMB, which coincides with clinical stratification. Remarkably, the high mutation group has more neutrophils, γδ T cells, fewer NK cells, and an inflammation profile. Reactive oxygen species (SBS18) are mainly found in NB, especially in the high mutation group, and are associated with systemic inflammation. <h3>Conclusions</h3> Based on tumor genomic data and systemic immune-related indicators, these findings illuminate the intricate interplay between TMB, mutational signatures, clinical characteristics, the tumor microenvironment, and systemic immune states in pediatric cancers. This understanding holds significant implications for the future treatment and early diagnosis of pediatric tumors.