The Immune landscape of pediatric solid tumors

Abstract

AbstractBackgroundImmunotherapy is quickly coming to the forefront of cancer treatment; however, the implementation of immunotherapy in solid pediatric cancers, which classically display a low mutational load, is hindered by insufficient understanding of the determinants of cancer immune responsiveness in children. In order to better understand tumor-host interplay, we sought to characterize solid pediatric cancers based on immunological parameters using analytes extracted from gene expression data.MethodsWe used RNAseq data from the publicly available TARGET studies for five pediatric solid tumor types (408 patients): Wilms tumor (WT), neuroblastoma (NBL), osteosarcoma (OS), clear cell sarcoma of the kidney (CCSK) and rhabdoid tumor of the kidney (RT). We assessed the performance of previously identified immune signatures like the Immunologic Constant of Rejection (ICR), which captures an active Th1/cytotoxic response associated with favorable prognosis and responsiveness to immunotherapy. We also performed gene set enrichment analysis (ssGSEA) and clustering, using more than 100 immune signatures to define immune subtypes in pediatric tumors and compared the overall survival across subtypes. The expression of immune checkpoints and enrichment of oncogenic pathways were also assessed across the immune subtypes.ResultsThe five tumor types showed distinct ICR score distributions. A higher ICR score was associated with better survival in OS and NBL-HR-MYCN_NA, but with poorer survival in WT. The clustering of immune signatures revealed the same five principal modules observed in adult solid tumors: Wound Healing, TGF-B signaling, IFN-G signaling, Macrophages, and Lymphocytes. These modules clustered pediatric patients into six immune subtypes (S1-S6) with distinct survival outcomes. The S2 cluster showed the best overall survival and was characterized by low enrichment of the wound healing signature, high Th1, low Th2. Conversely, cluster S4 showed the worst survival and highest enrichment of wound healing signature, low Th1, and high Th2. Furthermore, the upregulation of the WNT/Beta-catenin pathway is associated with unfavorable outcomes and lack of T-cell infiltration in OS.ConclusionsWe demonstrated that extracranial solid pediatric tumors could be classified according to their immune disposition, unveiling similarity with adults’ tumors. Immunological parameters might be explored to refine diagnostic and prognostic biomarkers and to identify potential immune-responsive tumors.