Uncovering the multi-faceted role of the tumor microenvironment with single-cell genomics: from identification of therapeutic targets to drivers of malignant cell states

Abstract

Human cancer biology and response to therapy are driven by the diverse ecosystem of malignant and non-malignant cell types that compose a human tumor. Since the advent of single- cell genomics, this technique has been widely applied to study human malignancies and has highlighted the heterogeneity of the malignant cell population and the influence of the tumor microenvironment on malignant cell function and response to immunotherapy. These advances have deepened our understanding of the underlying biology, yet many malignancies remain difficult to treat. This dissertation will discuss two single-cell transcriptomics studies aimed at further understanding two such malignancies: primary brain tumors (gliomas) and Ewing sarcoma, a rare pediatric malignancy. Chapter 1 presents a scRNA-seq study of glioma infiltrating T cells, where characterization of the T cell states identifies a novel therapeutic target present not only in gliomas but in other human malignancies. Chapter 2 focuses on the characterization of malignant cells in Ewing sarcoma and finds that a subset of malignant cell states are driven by interactions with the tumor microenvironment and predicts a worse prognosis.