This study aims to enhance our understanding of the tumor immune microenvironment (TIME) in pediatric solid tumors, using the Immune PAediatric Signature Score (IPASS) gene signature [1]. We focus on identifying immunosuppressive mechanisms, particularly the LIF-LIFR pathway, that contribute to immune exclusion in pediatric cancers.
Leveraging data from the ZERO Childhood Cancer program, including bulk RNA sequencing and whole genome sequencing, we deconvoluted immune cell beyond T cells, calculated immune scores including IPASS, and explored associations between genomic alterations and immune features. Matched bulk and single-cell RNA sequencing were employed to investigate immune cell infiltration, cellular communication, and mechanisms of immune exclusion highlighted by IPASS. To spatially resolve the TIME, we used spatial transcriptomics (10X Genomics Visium) and proteomics (Imaging Mass Cytometry and Opal multiplex), focusing on immune cell infiltration or exclusion driven by LIF-LIFR signaling.
Our analysis revealed a complex immune landscape in pediatric gliomas and renal cancers. The IPASS gene signature identified key immunosuppressive cell types, such as myeloid-derived suppressor cells and tumor-associated macrophages. Integration of whole genome sequencing data allowed us to identify genomic alterations associated with these immunosuppressive features. Single-cell RNA sequencing confirmed that the LIF-LIFR pathway plays an active role in these populations, contributing to the suppression of anti-tumor immune responses. Spatial analyses highlighted regions of immune exclusion associated with elevated LIF and LIFR expression.
This study demonstrates the effectiveness of a multiomic approach in unraveling the intricate immune environment of pediatric solid tumors. By focusing on the IPASS gene signature and LIF-LIFR pathway, and incorporating genomic alterations, we identified promising targets for enhancing anti-tumor immunity. Our findings provide insights into immune exclusion mechanisms in pediatric gliomas and renal cancers, paving the way for personalized immunotherapeutic strategies. Future research will validate these findings and explore their clinical potential.