PS2 - 217 Treatment of Glioblastoma Brain Tumor-Initiating Cells with Microglial and Macrophage-Derived Cytokines

Abstract

The most common brain cancer, glioblastoma (GBM), also has the worst five-year survival rates of all cancers. This is due in part to cancer stem cells, known as brain tumor initiating cells (BTICs), which initiate GBM and are resistant to current therapies. Thus, it is important to study therapeutics targeting BTICs. Innate immune cells, microglia and macrophages (MMs), are also important GBM-associated cells. GBM influences MMs to promote tumor growth. However, my research group discovered that an old drug, amphotericin B, re-stimulates MMs to secrete cytokines that inhibit BTIC self-renewal (Nature Neurosci 17:46-55, 2014). Hence, I hypothesize these cytokines are potential GBM treatments. Methods: Twenty genetically diverse BTIC lines were exposed to interleukin-8 (IL8), monocyte chemoattractant protein-1 (MCP1), and tumor necrosis factor-alpha (TNF), the cytokines secreted most abundantly by amphotericin-stimulated MMs. Assays for proliferation, differentiation, apoptosis, and cell cycle arrest were performed. BTICs were then co-cultured with human GBM-derived MMs stimulated with TNF. Lastly, the relationship between TNF receptors (TNFR1/2) and presumed BTICs was determined in frozen human GBM sections by immunofluorescence. Results: TNF had the most potent inhibitory effect on BTIC proliferation. Also, TNF was able to increase BTIC differentiation, and induce apoptosis and G1 cell cycle arrest. In MM-BTIC co-culture, TNF stimulated MMs to decrease sphere formation. Interestingly, in human GBM tissue TNFR1 co-labeled with OLIG2, a major transcription factor expressed in presumed BTICs, implicating TNF as a BTIC-specific treatment. Conclusion: TNF is a promising candidate for the treatment of GBM.