Regulation of the Tumor Immune Cell Landscape by Ciliated Glioblastoma Cells

项目摘要 胶质母细胞瘤(GBM)是成人最常见和最致命的脑癌，通常会复发。 治疗包括手术、化疗和放射治疗。问题的一个主要部分是GBMS雇用 抑制宿主免疫系统的各种机制，防止免疫细胞(如细胞毒效应器 T细胞)来破坏和移除癌细胞。据认为，肿瘤细胞释放或抑制信号 各种因素。因此，更好地了解肿瘤和肿瘤之间的细胞和分子串扰机制 免疫细胞类型是促进针对脑肿瘤的免疫治疗方法所必需的。值得注意的是，我们 和其他人报告说，标准护理化疗刺激形成的初级纤毛，一个 细胞器既被比作细胞的‘天线’，又被比作发射器。纤毛的存在预示着更多 侵袭性和耐治疗的GBM。我们现在第一次在病人的活组织检查中显示，胶质瘤- 相关的免疫细胞延伸接触肿瘤纤毛和纤毛尖端的过程，从而定位为发送 向GBM单元发送信号或从GBM单元接收信号。在脑内携带GBM的小鼠身上也观察到了类似的现象。 我们检测到纤毛与新招募的免疫细胞并列排列。值得注意的是，纤毛不成比例地 主要与单核细胞-MDSCs(M-MDSCs)有关，这是一种已知的T细胞抑制细胞类型 活动。相反，T细胞很少与肿瘤纤毛并列，并与纤毛保持较远的距离。 肿瘤细胞与M-MDSCs的比较。我们令人信服的数据表明了串扰的潜在机制 纤毛肿瘤细胞和促进肿瘤进展和治疗的特定免疫抑制细胞类型 抵抗。我们的工作假设是，GBM纤毛是调节与M-MDSCs相互作用的场所， 这种相互作用支持他们的T细胞抑制活性。我们研究的目的将决定1)如何 GBM纤毛影响M-MDSC和T细胞肿瘤的侵袭和功能；2)哪些免疫细胞类型接触或 避免人的基底膜中有纤毛的肿瘤细胞。我们将通过对同基因小鼠进行免疫表型鉴定来实现这些目标 有或没有纤毛的胶质瘤，并将这些发现与免疫微环境的空间分布进行比较 GBM患者标本中纤毛状瘤细胞周围。成功的结果将揭开一种新的细胞--细胞的面纱 脑肿瘤微环境中的相互作用可能部分解释了肿瘤细胞如何通过 免疫系统。

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.