Understanding the role of triggering receptor expressed on myeloid cells 2 (TREM2) on microglia and macrophages in gliomas

PROJECT SUMMARY/ABSTRACT: Gliomas are the most common brain cancer diagnosis in adults. They are often highly aggressive, and gliomas frequently recur after chemoradiation and surgical resection. Despite advances in immunotherapy improving outcomes for many other solid tumors, immune checkpoint blockade has not yielded widespread benefits for glioma patients. The brain tumor microenvironment is comprised of mostly myeloid cells including microglia and macrophages, which have been shown to either promote or restrain glioma progression. Neuroimmune modulators controlling this phenotypic switch must be better understood to develop effective glioma treatments. This proposal focuses on the role of triggering receptor expressed on myeloid cells 2 (TREM2) on microglia and macrophages in gliomas. TREM2 is a critical neuroimmune receptor implicated in governing microglial phenotypes in neurological disorders. TREM2 has also been studied in cancer, where its expression on macrophages dampens the anti-tumor immune response. Previous literature has shown that Trem2’s role in gliomas is complex, with some studies reporting it to be pro-tumor and our research indicating it promotes anti- glioma phagocytosis and antigen presentation. Therefore, further research is warranted to understand how variables including cell type and tumor stage affect TREM2 function. In Aim 1, I will use bone marrow chimera mice to understand how Trem2 expression on brain-resident and peripheral myeloid cells affects glioma growth and phagocytic uptake. In Aim 2, I will use genetically modified mouse models to determine how microglia and macrophage-specific Trem2 contribute to glioma outcomes and cellular phenotypes across tumor progression. During this fellowship, I plan to publish one first author review and two first author research papers. This study will be carried out at the University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences, a unique environment that allows me to train under world-class scientists in both neuroscience and cancer research. The state-of-the art facilities in the labs of my sponsor and co-sponsor will enable me to learn techniques including bone marrow transplantation, multi-photon in vivo imaging, and behavior analysis. I will participate in seminars at the UTHealth Houston Center for Neuroimmunology and Glial Biology and present this research at national conferences yearly. Therefore, this fellowship will contribute to the scientific training of the PI as well as the broader field of neuroimmune dynamics in gliomas. This proposal will advance our understanding of TREM2’s cell type dependent effects on gliomas across disease progression to determine if and when TREM2-targeting strategies are viable therapeutics for brain tumors.