Dissecting Orchestrated Immune Responses to Glioblastoma within the Native Tissue Microenvironment to Improve Treatment Outcomes

Project Summary The interpatient and intratumoral cellular heterogeneity of glioblastoma (GBM) is a major driver of up front therapy resistance and responsible for GBM’s brief median survival (~15 months). We and others have discovered that the transcriptomes of neoplastic GBM cells is heavily influenced by their anatomical localization. This led us to hypothesize that neoplastic and immune cellular composition and function is directly linked to their location within the tumor microenvironment (TME). Although recent single-cell RNA-sequencing (scRNAseq) studies have provided broad characterization of the cellular makeup and evolution of GBM tumor cells, dissecting the diversity, function and regional localization of the neoplastic and immune composition of GBM remains incomplete. There is also an unfortunate lack of knowledge on the evolution of intratumoral neoplastic and immune cells during GBM progression, and throughout treatment with standard of care therapy that is composed of ionizing radiation, temozolomide and dexamethasone. Therefore, a mechanistic understanding of the effects of standard of care therapy on immune and neoplastic cell population dynamics in pre-clinical mouse models of GBM in combination with analysis of archival human patient GBM samples will yield transformative advancements in the field. In this proposal, we will leverage archival patient samples and mouse models of GBM to uncover SOC-related cellular and molecular evolutionary changes using single cell spatial transcriptomics and proteomics. By integrating detailed spatial mouse and human data with high granularity, we will identify tumor microenvironment areas of unrecognized therapeutic vulnerabilities and pave the way for the development of new treatment approaches.