Sunday, November 24, 2024
11/24/2024
Project Summary Glioblastoma (GBM) is the most common and aggressive malignant brain tumor in adults and is virtually incurable. Despite aggressive treatments that include surgery, radiation therapy, and chemotherapy, the average survival is 15.4 months, with less than 5% of patients surviving > 5 years. Immunotherapy is a promising new approach to treat GBM as it harnesses one’s own immune system to recognize and kill aberrant cancer cells. Unfortunately, ongoing trials with immunotherapies show disappointing results in most GBM patients, indicating that we need to better understand the intricate and dynamic interactions between glioma and immune cells that generate and maintain highly immune suppressive microenvironment in GBM. The major goal of this application is to test our hypothesis that S100A4 is a critical regulator of the GBM immune landscape. S100A4 is a small calcium binding protein that functions intracellularly as well as extracellularly. We recently reported that S100A4 is necessary for human and mouse glioma stem cell self- renewal. Our single cell RNA-sequencing analyses of human GBM shows that S100A4 is expressed in both glioma cells and immune suppressive leukocytes. Consistently, TCGA data analyses indicate that S100A4 expression is strongly correlated with primary and recurrent GBM patient survival, the mesenchymal subtype, and immune-suppressive macrophage markers (such as CD163, CD206, and IL10). Importantly, our unpublished results show that S100A4 in human and mouse glioma cells regulates expression of chemokines and cytokines that control immune cell infiltration and polarization towards immune suppressive phenotypes. Notably, knocking down S100a4 in glioma cells is sufficient to reprogram the immune environment and allow dramatic increase in T-cell infiltration and activation in mouse gliomas. Furthermore, deletion of S100a4 in the host mouse is also sufficient to reprogram the glioma immune landscape and extend survival (manuscripts in preparation). Therefore, we hypothesize that S100A4 functions in both glioma and immune to promote immune-suppressive environment in GBM through multiple mechanisms. To test this hypothesis, we will: 1) elucidate mechanisms through which S100A4 expression in glioma cells promotes local immune-suppressive microenvironment in GBM (Aim 1); and 2) determine mechanisms through which S100a4 expression in immune cells controls myeloid and T cell trafficking, polarization, and function (Aim2). Successful completion of this study will reveal how S100A4 regulates glioma associated immune cell infiltration/polarization and identify a potential novel immunotherapy target to treat GBM.
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