Role of the collagen receptor LAIR-1 in glioma progression and the tumor immune microenvironment

摘要 高级别胶质瘤(HGG)是所有原发脑肿瘤中最致命的。他们是不治之症，中位存活率 在18-24个月之间。胶质瘤渗入肿瘤周围的健康脑组织。因此，即使这些 肿瘤不转移，患者死于局部肿瘤复发。胶原蛋白是心脏的核心成分 高级别胶质瘤的细胞外基质，促进肿瘤的侵袭和生长。他们如何做到这一点是复杂的， 而且还没有完全被理解。胶原蛋白通过物理作用为细胞外基质提供结构硬度 机械装置。除了物理机制外，生物化学上的胶原蛋白还影响细胞内机制。 胶原蛋白通过与大量的胶原蛋白受体相互作用而影响细胞内信号转导。这些受体 它们是：整合素、盘状结构域受体DDR1和DDR2、GPVI、MRC2和LAIR-1。白细胞相关 免疫球蛋白样受体-1(LAIR-1)是一种跨膜糖蛋白，其胞外段含有一个 单个免疫球蛋白样(Ig样)结构域，其胞内片段具有两个免疫受体酪氨酸- 基于抑制基序(ITIMs)。LAIR-1在T细胞、B细胞、自然杀伤(NK)细胞、 巨噬细胞和其他免疫细胞。LAIR-1强烈抑制免疫细胞激活，从而减少 免疫反应。富含胶原的肿瘤，特别是I型和III型胶原，激活CD8+T细胞中的LAIR-1，以及 降低T细胞介导的细胞毒作用。因此，LAIR-1对免疫细胞的激活被认为是一种 肿瘤抑制抗肿瘤免疫反应的机制。令人惊讶的是，我们发现LAIR-1也是 在胶质瘤细胞中表达。LAIR-1在宫颈癌、乳腺癌、肾癌等实体瘤中的表达 增加肿瘤的侵袭性。因此，我们推测LAIR-1可能通过直接影响神经胶质瘤的进展。 增强肿瘤细胞的致病作用，并间接通过抑制抗肿瘤的细胞毒免疫 回应。基因工程小鼠胶质瘤模型胶原基因敲除后中位数增加 存活，并减少脑肿瘤内LAIR-1的表达。因此，胶原蛋白可以直接抑制胶质瘤的生长。 免疫反应，或影响胶质瘤细胞的恶性行为。因此，迫切需要一种机械式的 了解浸润性免疫细胞或胶质瘤细胞表达LAIR-1是如何促进 胶质瘤的进展和侵袭，以及它如何重塑肿瘤免疫微环境。我们的长期目标 是了解细胞外肿瘤基质是如何通过其胶原蛋白的表达影响肿瘤进展的 和抗肿瘤免疫。我们在这个应用程序中的总体目标是测试LAIR-1的假设 在胶质瘤细胞中的表达促进肿瘤进展(AIM-1)，LAIR-1的表达在调节 浸润性免疫细胞(AIM-2)的功能，并确定抑制LAIR-1的治疗潜力 脑胶质瘤模型(AIM 3)。我们的中心假设是LAIR-1起着重要的病理作用 通过在胶质瘤细胞和免疫细胞中的表达及抑制LAIR-1而促进胶质瘤的进展 信号转导可以发现治疗HGG的新靶点。

ABSTRACT High-grade gliomas (HGG) are the deadliest of all primary brain tumors. They are incurable and median survival is between 18-24 months. Gliomas infiltrate the healthy brain tissue surrounding the tumor. Thus, even if these tumors do not metastasize, patients die due to local tumor recurrence. Collagens are a central component of the extracellular matrix of high-grade gliomas, and promote invasion and tumor growth. How they do so is complex, and not fully understood. Collagen provides structural stiffness to the extracellular matrix, through physical mechanisms. In addition to physical mechanisms, biochemically collagen affects intracellular mechanisms. Collagen affects intracellular signaling by interacting with a large number of collagen receptors. These receptors are: integrins, discoidin domain receptors DDR1 and DDR2, GPVI, MRC2 and LAIR-1. Leukocyte-associated immunoglobulin-like receptor-1 (LAIR- 1) is a transmembrane glycoprotein, its extracellular segment contains a single immunoglobulin-like (Ig- like) domain, and its intracellular segment has two immuno- receptor tyrosine- based inhibitory motifs (ITIMs). LAIR-1 is strongly expressed on T cells, B cells, natural killer (NK) cells, macrophages and other immune cells. LAIR-1 strongly suppresses immune cell activation, thus reducing immune responses. Collagen-rich tumors, especially collagens I and III activate LAIR-1 in CD8+ T cells, and reduce T cell-mediated cytotoxicity. Thus, activation of LAIR-1 on immune cells has been proposed as a mechanism by which tumors inhibit antitumor immune responses. Surprisingly, we found that LAIR-1 is also expressed in glioma cells. Expression of LAIR-1 in other solid tumors, such as cervical, breast and kidney cancer increases tumor aggressiveness. Thus, we postulate that LAIR-1 could affect glioma progression by directly increasing the pathogenesis of cancer cells, and indirectly, by inhibiting the anti-tumor cytotoxic immune responses. Knockdown of collagen from genetically engineered mouse models of glioma increased median survival, and reduced LAIR-1 expression within brain tumors. Thus, collagen could directly inhibit anti-glioma immune responses, or affect the malignant behavior of glioma cells. There is thus a critical need for a mechanistic understanding of how LAIR-1 expressed by either infiltrating immune cells or glioma tumor cells contributes to glioma progression and invasion and how it remodels the tumor immune microenvironment. Our long-term goal is to understand how the extracellular tumor matrix, through its expression of collagen affects tumor progression and anti-tumor immunity. Our overall objectives in this application are to test the hypothesis that LAIR-1 expression in glioma cells increases tumor progression (AIM 1), the role of LAIR-1 expression in regulating the function of infiltrating immune cells (AIM 2), and determine the therapeutic potential of the inhibition of LAIR-1 in glioma models (AIM 3). Our central hypothesis is that LAIR-1 plays essential pathological roles that contribute to glioma progression through its expression in glioma cells and in immune cells and that inhibiting LAIR-1 signaling could uncover novel therapeutic targets for HGG.