Wednesday, May 15, 2024
5/15/2024
PROJECT SUMMARY: Myeloid cells are one of the most abundant immune infiltrates in the glioblastoma (GBM) tumor microenvironment (TME); they can constitute 20-30% of the tumor mass and are either of hematopoietic origin or are tissue- resident. Myeloid cells play a crucial role in shaping the TME, promoting tumor growth, regulating adaptive immunity, and in response to therapy. Due to these significant roles, myeloid cells are an essential subject of intensive research and therapeutic target development. However, targeting tumor-associated myeloid cells has been remarkably challenging. One of the critical factors underlying this difficulty is our incomplete understanding of their heterogeneity and of the interactions between various myeloid subsets. This application is focused on myeloid subsets, referred to as monocytes and neutrophils, which infiltrate tumors from the blood circulation and differentiate into tumor-associated macrophages and tumor-associated neutrophils. We provide evidence that both populations infiltrate GBM, but that their composition differs; while monocytes are enriched in Proneural and Classical GBM, Mesenchymal GBM shows increased neutrophils in addition to increased microglia presence. Using genetically-engineered mouse models driven by human GBM-specific driver mutations, we discovered that tumor growth was not impaired when the influx of monocytes was abolished in murine Proneural monocyte-enriched GBM due to compensatory recruitment of neutrophils, which resulted in PN-> MES transition of tumors. We hypothesize that although monocyte and neutrophil infiltration differ in various GBM subtypes, they share many common tumor-promoting and immunosuppressive functions. Thus, targeting one population will lead to infiltration of the other, but targeting both will lead to impaired tumor growth, increased activation of T-cells, and improved immune surveillance. To address our hypothesis, we will: (1) determine how the spatial and genetic heterogeneity of GBM affects myeloid infiltration and expression profiles using single-cell RNA- sequencing, spatial multiomics, and multiplex FACS with a major focus on neutrophils in the presence and absence of monocyte infiltration. We will functionally characterize myeloid subsets, test their immunosuppressive properties, and identify how TNFa signaling and/or other neutrophil-driven gliomagens regulate neutrophil-tumor crosstalk to promote GBM growth in the presence or absence of monocytes; and (2) determine the biological significance on GBM tumor growth and immunity when infiltration of both myeloid subsets from blood is abolished. These studies have the potential to help us to understand better the remaining challenges of macrophage- and chemokine-targeted therapies in cancer. We will also determine the therapeutic efficacy of two small-molecule inhibitors targeting monocytes and neutrophil influx into tumors.
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