Abstract PR06: The immunogenomic landscape of pediatric primary solid tumors

Introduction: Immune checkpoint inhibition is a novel approach of restimulating immune cells to overcome immunosuppressive microenvironment in tumors and has shown significant clinical benefit in 20-40% of adult patients. Although this success in adult cancers has resulted in a plethora of immunogenomic efforts to delineate mechanisms of response, such studies in pediatric cancers are lacking. The main objective of this study is to uncover the overall characteristics of immune microenvironment in pediatric solid tumors. Methods: We leveraged transcriptomes of 1,268 pediatric primary solid tumors acquired from multiple international initiatives, including Therapeutically Applicable Research to Generate Effective Treatments (TARGET, n = 269), International Cancer Genome Consortium (ICGC, n = 216) and Children Brain Tumor Tissue Consortium (CBTTC, n = 803). We compared our results with those of 7 adult cancer types from The Cancer Genome Atlas (TCGA, n = 2720). We applied methods of immune deconvolution, repurposed RNAseq data to recover infiltrating T- and B-cell clonotypes and studied checkpoint gene expression in pediatric tumors. In collaboration with Gabriela Miller’s Kids First Data Resource Centre, all analyses were performed and shared on CAVATICA computational platform (cavatica.sbgenomics.com). Results: Embryonal tumors with multilayered rosettes (ETMR) and medulloblastomas (MB) harbored the lowest levels of immune infiltration in our pediatric cohort. Immune deconvolution analysis revealed that neuroblastomas (NBL) had the highest T-cell infiltration amongst pediatric cancers. We found atypical teratoid/rhabdoid tumors (ATRT) had highest levels of CD8+ T cells among pediatric CNS tumors. While tumor mutational burden (TMB) was associated with immune cell infiltration in adult lung cancers and melanomas, we found no significant association in pediatric cancers. We found specific genetic alterations such as BRAF, H3F3A, and CTNNB1 had significant impact on the composition of the immune microenvironment. Analysis of T-cell repertoire revealed an inverse correlation between clonal diversity and TMB, suggesting a T-cell clonal expansion in high TMB samples. Finally, while the majority of NBL samples expressed LAG3, ~10% of samples had elevated levels of TIM3 gene, suggesting a distinct mode of immunosuppression in this subset. 2% of pediatric CNS tumors, mostly consisted of ATRTs, harbored high expression of PRF1 and GZMA genes suggestive of functionall