Prognostic Gene Expression, Stemness and Immune Microenvironment in Pediatric Tumors

Abstract

Pediatric tumors frequently arise from embryonal cells, often displaying a stem cell-like (“small round blue”) morphology in tissue sections. Because recently “stemness” has been associated with a poor immune response in tumors, we investigated the association of prognostic gene expression, stemness and the immune microenvironment systematically using transcriptomes of 4068 tumors occurring mostly at the pediatric and young adult age. While the prognostic landscape of gene expression (PRECOG) and infiltrating immune cell types (CIBERSORT) is similar to that of tumor entities occurring mainly in adults, the patterns are distinct for each diagnostic entity. A high stemness score (mRNAsi) correlates with clinical and morphologic subtype in Wilms tumors, neuroblastomas, synovial sarcomas, atypical teratoid rhabdoid tumors and germ cell tumors. In neuroblastomas, a high mRNAsi is associated with shortened overall survival. In Wilms tumors a high mRNAsi correlates with blastemal morphology, whereas tumors with predominant epithelial or stromal differentiation have a low mRNAsi and a high percentage of M2 type macrophages. This could be validated in Wilms tumor tissue (n = 78). Here, blastemal areas are low in M2 macrophage infiltrates, while nearby stromal differentiated areas contain abundant M2 macrophages, suggesting local microanatomic regulation of the immune response.

DNA Methylation Data-Based Classification and Identification of Prognostic Signature of Children With Wilms Tumor

“…Increasing studies have shown that TIICs in WT are related to the initiation and prognosis of WT (Maturu et al, 2017;Fiore et al, 2021;Stahl et al, 2021). Oleinika et al found that immune dysregulation contributes to the pathogenesis of many kidney diseases, regardless of antibody involvement (Oleinika et al, 2019).…”

“…Comprehensive profiling that includes stage, histology and DNA methylation analysis during clinical diagnosis may help clinicians to evaluate the disease progression and select appropriate therapeutic strategies to treat WT in children. Numerous studies have focused on the pivotal role played by the tumor microenvironment in the initiation and progression of WT (Maturu et al, 2017;Fiore et al, 2021;Stahl et al, 2021), therefore, we also analyzed the level of immune infiltration in high-and low-risk groups to evaluate the potential correlation between methylation and immune infiltration in WT.…”

The Growing Relevance of Immunoregulation in Pediatric Brain Tumors

“…Furthermore, several studies examined the influence of infiltrating immune cells on patients’ prognosis [ 18 , 19 , 20 , 22 , 65 ] ( Table 1 ). For example, among MB subgroups TAMs are enriched in SHH-MB patients, having an antitumoral role [ 66 ].…”

“…Moreover, WNT and SHH pathways are associated with a stemness-enriched tumor profile, and stemness, in turn, was linked to resistance to immune-mediated destruction [ 89 ]. ATRT-SHH tumors showed a higher stemness score than other ATRT subtypes and were highly infiltrated by myeloid cells [ 18 , 19 ]. In glial tumors, CD3+ T cell infiltration correlates inversely with the expression of SOX2 , an embryonal stem cell marker commonly expressed by glial tumors [ 17 ].…”

“…However, recent efforts have shown that antitumor immune control exists in pediatric brain tumors, e.g., rhabdoid tumors and LGG showed strong T cell infiltration [ 15 , 16 , 17 ]. Moreover, several studies present prognostications of specific immune cell infiltrates on overall survival [ 18 , 19 , 20 , 21 , 22 ] ( Table 1 ). Thus, the indications that host immunity may already impact patients’ survival in pediatric brain tumors suggests that immune profiling can add valuable information in diagnostics and assessment of immunotherapeutic therapies for individual patients.…”