Regulation of the Tumor Immune Cell Landscape by Ciliated Glioblastoma Cells

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Project Summary Glioblastoma (GBM) is the most common and lethal form of brain cancer in adult, typically recurring after all therapies including surgery, chemotherapy, and radiation. A major part of the problem is that GBMs employ various mechanisms to suppress the host immune system, preventing the immune cells (e.g., cytotoxic effector T cells) from destroying and removing cancer cells. It is believed that tumor cells release or signal suppressive factors. Thus, a better understanding of the cellular and molecular crosstalk mechanisms between tumor and immune cell types are needed to advance immunotherapeutic approaches against brain tumors. Notably, we and others have reported that standard of care chemotherapy stimulates formation of primary cilia, an organelle that is likened to both a cellular ‘antenna’ and transmitter. The presence of cilia predicts more aggressive and treatment resistant GBM. We now show for the first time, in patient biopsies, that glioma- associated immune cells extend processes that contact the tumor cilia and cilia tip, thus positioned to send signals to or receive signals from GBM cells. Similar observations were made in intracranial GBM-bearing mice where we detected juxtaposition of cilia with recruited immune cells. Notably, cilia disproportionately and predominately associated with monocytic-MDSCs (M-MDSCs), a cell type with known T cell suppressive activity. In contrast, T cells rarely juxtaposed tumor cilia and maintained greater distances away from ciliated tumor cells compared to M-MDSCs. Our compelling data suggest potential mechanisms of crosstalk between ciliated tumor cells and specific immune-suppressive cell types that promote tumor progression and therapy resistance. Our working hypothesis is that GBM cilia are venues for mediating interactions with M-MDSCs, and this interaction supports their T cell suppressive activity. The aims of our studies will determine 1) how GBM cilia affect M-MDSC and T cell tumor infiltration and function, and 2) which immune cell types contact or avoid ciliated tumor cells in human GBM. We will tackle these aims by immunophenotyping syngeneic murine gliomas with or without cilia, and compare these findings to spatial profiling of the immune microenvironment around ciliated tumor cells in GBM patient specimens. Successful outcomes will shed light on a novel cell-cell interaction in the brain tumor microenvironment that may explain, in part, how tumor cells evade targeting by the immune system.