PATH-30. BIOLOGIC AND CLINICAL SIGNIFICANCE OF NEOPLASTIC AND IMMUNE CELL STATES IN GROUP3 AND GROUP 4 MEDULLOBLASTOMA

Abstract

Abstract Medulloblastoma (MB) is a heterogeneous malignant childhood brain cancer, classified into four molecular subgroups, WNT, SHH, Group3, and Group4, based on transcriptional, genetic, and clinical features. We aimed to understand the tumor microenvironment of Group 3 and Group 4 tumors utilizing single-cell transcriptome data. We identified four neoplastic cell states, including stemness (TNF-α), proliferative, mesenchymal and quiescence, and 11 broad lymphoid and myeloid cell types from single-cell transcriptomes. We applied CIBERSORTx to enumerate cell type proportion and CODEFACS on 73 bulk MB RNAseq profiles to determine cell type-specific abundance and gene expression profiles. We noted significant associations (both positive and negative) between the abundance of neoplastic cell states and microenvironmental cell types in both group3 and group4 MB. For example, the invasive cell state negatively correlated with dendritic cells in Group3 and Group4 tumors, but the invasive cell state was oppositely correlated with a macrophage subset in group 3 versus group 4 tumors, Survival analysis showed a significant association of higher proliferative cell state with poorer survival in Group3 MB while in group4 elevated invasive cell state, as well as elevated α, NK, and CD4-T cell abundance showed trends for poorer prognosis. Using Ecotyper, we determined cellular ecotypes based on cell type-specific transcriptome states. An ecotype containing B cell, hematopoietic, dendritic, and proliferative cell states was associated with poor prognosis in group3 and group4 tumors. We further analyzed ligand-receptor interaction between cell type states of poor prognosis ecotype; and found several interactions between ligands from immune cells (SEMA4G, LAMB2) and receptors on neoplastic cells (PLXNB2). Conversely, extracellular matrix ligands on neoplastic cells (COL1A1/2 and FN1) were found on this analysis potentially associated with integrin receptors on immune cells. Overall, our study highlights the potential biologic and clinical significance of neoplastic and immune cell states in group3/4 MB.