Browsing by Author "Poon, Candice Cassia"

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    Characterization and Therapeutic Manipulation of Glioblastoma-Associated Microglia, Macrophages, and Cytokines to Improve Prognosis
    (2020-01-30) Poon, Candice Cassia; Kelly, John James Patrick; Yong, Voon Wee; Cairncross, Gregory J.; Chan, Jennifer A. W.
    Glioblastoma comprises the majority of malignant primary adult brain tumors and has one of the worst survival rates of all cancers. The poor prognosis is a product of the transformed cells acting in collusion with the tumor microenvironment, a large component of which are inflammatory infiltrates. Glioblastoma-associated microglia and macrophages (GAMMs) predominate this immune infiltrate, making them important considerations for tumor biology and therapy. These innate immune cells are meant to participate in tumor surveillance and eradication, but they become compromised by glioblastoma and exploited in the process. However, the phenotypic variability of GAMMs has not been well characterized in the two major groups of glioblastoma, isocitrate dehydrogenase (IDH)-mutated and wildtype tumors. Furthermore, whether pro-inflammatory, anti-tumor cytokines secreted by healthy microglia and macrophages can alter the progression of glioblastoma by targeting cancer stem cells known as brain tumor-initiating cells (BTICs) is not well-developed as a therapy. Lastly, there have been a paucity of glioblastoma-associated microglia and macrophage (GAMM) studies conducted with human tissue in favor of more accessible murine models. In this thesis, we sought to address these understudied topics. We developed an immunofluorescent imaging protocol that quantifies the expression of GAMM inflammatory markers and identifiers at the individual-cell level, although this method could be adapted to quantitate any immunofluorescent marker in slide-mounted tissues. Using this technique, flow cytometry, and analysis of publicly available single-cell RNA sequencing databases we discerned similarities and differences between human GAMMs in IDH-mutant and wildtype-glioblastomas. We found that macrophages may be the drivers of the anti-inflammatory, pro-tumor phenotype displayed by immune cells in the glioblastoma microenvironment. IDH-mutant tumors which have more favorable prognoses in contrast to wildtype tumors possessed more pro-inflammatory microglia. Not only does this suggest immunostimulants may be particularly promising therapies, but peripheral monocyte-derived macrophages may be targeted systemically instead of needing to create a blood brain barrier penetrant drug. We also investigated tumor necrosis factor alpha (TNF), a pro-inflammatory cytokine secreted by microglia and macrophages, as an anti-brain tumor-initiating cell (BTIC) therapy. Not only does TNF directly inhibit BTICs as a monotherapy, but in combination with the frontline chemotherapy for glioblastoma, temozolomide, acts in a combinatorial fashion to channel BTICs towards cellular demise. Significant challenges remain but treatments that affect and/or are derived from glioblastoma-associated microglia and macrophages hold considerable promise to improve the prognosis for patients with this disease.