Saturday, December 3, 2022
12/3/2022
Project Summary Gliomas are the most common brain cancer. Whereas malignant gliomas predominate in adults, low-grade gliomas (LGGs) comprise the majority of brain tumors in the pediatric population. While LGGs are not typically fatal, young children with these neoplasms commonly have long-term medical morbidities, from either the tumor itself or the neurotoxicity associated with conventional therapies. This is particularly true for individuals with the Neurofibromatosis type 1 (NF1) cancer predisposition syndrome, where nearly 20% of children will develop LGGs involving the optic pathway (optic pathway gliomas; OPGs) that can lead to vision loss. Currently, therapies for NF1-LGGs are focused on arresting the growth of the cancer cells using either genotoxic (e.g., carboplatin/vincristine) or molecularly targeted (e.g., MEK inhibitors) treatments, with variable durable effects. Importantly, 30-50% of the cells in human NF1-LGGs are non-neoplastic cells, such as neurons, lymphocytes (T cells) and monocytic cells (macrophages and microglia), which our laboratory has shown are required for both tumor formation and growth in experimental murine models of Nf1-OPG. Using these Nf1-OPG mouse strains, we have previously defined a “neuron-immune-cancer cell circuit” in which Nf1-mutant neurons activate T cells to produce cytokines that stimulate microglia to support LGG formation and continued growth. Specifically, we demonstrated that NF1-mutant human and murine neurons produce midkine, which activates T cells in vitro and in vivo to secrete Ccl4, which then acts on microglia to induce Ccl5 expression, an essential growth factor for Nf1-OPG formation and growth. Surprisingly, we found that CD8+ T cells predominate in both human and mouse NF1-LGG, where high CD8, but not CD4, levels correlate with reduced overall survival in people with LGG. Moreover, studies in our laboratory revealed that antibody-mediated CD8+ T cell depletion reduces mouse Nf1- OPG growth in vivo. Based on these findings, we hypothesize that CD8+ T cells function in a neuron- immune-cancer cell circuit as obligate modulators of LGG development and progression. To test this hypothesis, we have designed a series of experiments we have designed a series of experiments that aim to (a) define the immune composition of Nf1 optic gliomas in mice, (b) determine why CD8+ T cells are selectively recruited in these murine brain tumors, and (c) elucidate how NF1 mutation in neurons modifies T cell-microglia interactions. Collectively, these studies aim to mechanistically dissect the role of CD8+ T cells in neuron-immune- cancer cell axis regulation of LGG formation and growth, relevant to the development of future immunomodulatory therapeutic strategies. OMB No. 0925-0001/0002 (Rev. 03/2020 Approved Through 02/28/2023) Page 1 Continuation Format Page
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