Identifying Prognostic Cell State Interactions in the TumorMicroenvironment of IDH-Mutant Gliomas Using CSI-TME

Intercellular communication between distinct transcriptional states of various cell types in the tumor microenvironment (TME) influence the progression and clinical outcome of the tumors. Details of such clinically relevant cellular state interactions (CSIs) in IDH-mutant gliomas remain obscure. Here we developed CSI-TME, a computational pipeline that deconvolves cell type-specific gene expression from bulk transcriptomic data, identifies distinct cell states, and uncovers prognostic cell state interactions by modelling the clinical data based on the joint activity of cell state pairs. We found a significantly reproducible cell state interaction network (CSIN) that is (i) predominantly pro-tumor, (ii) likely mediated through the interaction between cell surface molecules, (iii) differentially activated in IDH-mut astrocytoma and oligodendroglioma, and (iv) significantly associated with response to immune checkpoint blockade therapy. The distinct malignant cell states involved in CSIs resembled neuronal lineages such as astrocyte-like and oligodendrocyte progenitor cells-like states and captured key interactions between glioma stem cells and immune cells. Integration of CSIN with somatic mutation data suggests the anti-tumor role of CSIs in the early stages that transitions towards pro-tumor role as glioma progresses. In summary, CSI-TME provides valuable insights into the physiology of the TME in IDH-mutant glioma and provides a framework to prioritize ligand-receptor interactions or patients stratification for therapeutic interventions.