Deciphering TREM1/2 Function in Primary Brain Cancer Using a New Model of Glioblastoma

Project Summary / Abstract Glioblastoma (GBM) is an incurable primary malignant brain cancer characterized by a high degree of interpatient and intratumoral genomic and cellular heterogeneity, a brief median survival (14 months), and absence of an effective treatment. One of the key aspects of GBM rapid growth and underlying resistance to

therapeutic interventions is its highly immunosuppressive tumor microenvironment (TME). Recent studies have also demonstrated an underappreciated effect of GBM on the immune system as a whole, in particular on the immune cells of the bone marrow. Here, we propose to perform exploratory studies on the role of two major

myeloid receptors, Trem1 and Trem2, in fine tuning the hematological responses of the bone marrow to the presence of GBM using a novel mouse model of GBM. We created a novel C57Bl6/J syngeneic model of EGFR-driven GBM that allows orthotopic allogenic engraftment in the CNS. We will use this model to study the

function of Trem1 and Trem2 in the emergency myelopoiesis response to GBM. Using conditional Cre/Lox alleles of Trem1 and Trem2 C57Bl6/J strains and cell specific Cre transgenic mice, we will selectively eliminate Trem1 and Trem2 in various myeloid compartments in the presence of GBM, and determine their

functions by analyzing the resulting GBM immune microenvironment composition and function by flow cytometry. We, and others have demonstrated that Trem1 is mostly expressed on granulocytes whereas Trem2 is mainly expressed on monocytes, macrophages and microglia. By eliminating the expression of Trem1 and Trem2 in their respective cell types, we will directly determine their potential as future targets for

pharmacological intervention in the treatment of GBM. This research will not only advance our knowledge of immune-based intervention for GBM clinical management but also will establish and solidify a new, genetically accurate and relevant mouse model of GBM.