S100A4 mediated immune suppression in GBM

项目摘要 胶质母细胞瘤（GBM）是成人中最常见和最具侵袭性的恶性脑肿瘤， 无法治愈尽管积极的治疗包括手术，放射治疗和化疗， 存活期为15.4个月，少于5%的患者存活> 5年。免疫疗法是一种很有前途的新疗法。 治疗GBM的方法，因为它利用自己的免疫系统来识别和杀死异常的癌细胞。 不幸的是，正在进行的免疫治疗试验显示，大多数GBM患者的结果令人失望， 我们需要更好地理解神经胶质瘤和免疫细胞之间复杂而动态的相互作用， 在GBM中产生并维持高度免疫抑制的微环境。 本申请的主要目的是检验我们的假设，即S100A4是GBM的关键调节因子 免疫景观S100A4是一种小的钙结合蛋白，其在细胞内以及细胞外起作用。 在细胞外。我们最近报道，S100A4是人类和小鼠胶质瘤干细胞自我调节所必需的。 退款我们对人GBM的单细胞RNA测序分析表明，S100A4在人GBM和人GBM中表达。 神经胶质瘤细胞和免疫抑制性白细胞。同时，TCGA数据分析表明，S100A4 表达与原发性和复发性GBM患者的存活率，间充质亚型， 和免疫抑制性巨噬细胞标志物（如CD 163、CD 206和IL 10）。重要的是我们的 未发表的结果表明，S100A4在人类和小鼠胶质瘤细胞中调节趋化因子的表达 以及控制免疫细胞浸润和向免疫抑制表型极化的细胞因子。 值得注意的是，在神经胶质瘤细胞中敲低S100a4足以重新编程免疫环境，并允许 小鼠神经胶质瘤中T细胞浸润和活化的显著增加。此外，S100a4的缺失在 宿主小鼠也足以重新编程神经胶质瘤免疫景观并延长存活（手稿在 制备）。因此，我们假设S100A4在胶质瘤和免疫中均起作用， 通过多种机制改善GBM中免疫抑制环境。为了验证这个假设，我们将： 1)阐明胶质瘤细胞中S100A4表达促进局部免疫抑制的机制 GBM中的微环境（目的1）;和2）确定免疫中S100a4表达的机制 细胞控制骨髓和T细胞运输、极化和功能（Aim2）。本研究的成功完成 将揭示S100A4如何调节胶质瘤相关的免疫细胞浸润/极化，并确定一个潜在的 新的免疫治疗靶点来治疗GBM。

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 Importantly, our unpublished results show that S100A4 in human and mouse glioma cells regulates expression of chemokines and cytokines that control immune cell infiltration and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.