Zarodniuk : Cancer-Associated Fibroblast-Like Cells Predict Response to Immunotherapy in Glioblastoma
Cancer-Associated Fibroblast-Like Cells Predict Response to Immunotherapy in Glioblastoma
University of Notre Dame
Maksym, Zarodniuk, Department of Aerospace and Mechanical Engineering, University of Notre Dame; Alexander, Steele, Department of Electrical Engineering, University of Notre Dame; Xin, Lu, Department of Biological Sciences, University of Notre Dame; Jun, Li, Department of Applied and Computational Mathematics and Statistics, University of Notre Dame
Excessive deposition of extracellular matrix (ECM) is a hallmark of solid tumors; however, it remains poorly understood which cellular and molecular components contribute to the formation of ECM stroma in central nervous system (CNS) tumors.
Here, we undertook a pan-CNS analysis of retrospective gene expression datasets to characterize inter- and intra-tumoral heterogeneity of ECM remodeling signatures in both adult and pediatric CNS disease.
We found that CNS lesions – glioblastoma in particular – can be divided into two ECM-based subtypes (ECMhi and ECMlo) that are influenced by the presence of perivascular cells resembling cancer-associated fibroblasts (CAFs). Ligand-receptor network analysis predicted perivascular fibroblasts activate signaling pathways that may be responsible for recruitment of tumor-associated macrophages, and may promote cancer stemness enrichment. Our analysis reveals that perivascular fibroblasts are correlated with unfavorable response to immune checkpoint blockade in glioblastoma and poor patient survival across a subset of CNS tumors.
Our study provides insights into novel stroma-driven mechanisms underlying immune evasion and immunotherapy resistance in CNS tumors like glioblastoma.
Translational/Human Health Impact:
CAF-mediated immune suppression mechanisms proposed in this study may reveal unique therapeutic vulnerabilities that can be targeted in future preclinical studies.