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.

Grant Number: 1R21NS139480-01
NIH Institute/Center: NIH
Principal Investigator: Alain Charest