Modulation of Microglia and T Cell Interactions in Malignant Glioma

摘要 免疫疗法通过逆转细胞毒性抗肿瘤抗体的免疫抑制，为癌症治疗带来了革命性的变化。 肿瘤CD8+效应T细胞。然而，胶质母细胞瘤患者有严重的淋巴细胞减少和免疫力。 检查点抑制治疗不能恢复T细胞免疫功能。我们小组广泛的人物刻画 已经证明，胶质母细胞瘤与其他恶性肿瘤相比有根本的不同。 募集到肿瘤中的巨噬细胞和小胶质细胞等天然免疫细胞的浓缩 微环境。这些先天免疫细胞对肿瘤有支持作用。在一种基因工程小鼠模型中 胶质母细胞瘤(GEMM)我们用CD8基因敲除(KO)背景重现淋巴组织，并发现 表达PD-1的巨噬细胞在小鼠脑胶质瘤微环境中的显著浓缩--类似于 对人脑胶质母细胞瘤患者的观察。我们评价了抗PD-1抗体传递的效果 在携带胶质母细胞瘤的野生型小鼠和CD8KO背景下静脉注射，发现具有治疗作用 即使在没有CD8效应T细胞的情况下也能受益。外周单核细胞来源的巨噬细胞和 抗PD-1抗体治疗的小鼠胶质母细胞瘤微环境中驻留的小胶质细胞减少。 因此，我们的总体研究假设是，抗PD-1发挥治疗性免疫调节作用 胶质母细胞瘤通过中枢神经系统(CNS)的先天免疫。这项提案将涉及多个 该领域的关键问题包括：1)抗PD-1抗体是否进入中枢发挥治疗作用； 2)除了CD8 T细胞外，还有哪些免疫细胞对该制剂的疗效有贡献；3)是 从外周产生的调节治疗效果的免疫细胞或它们是固有的 中枢神经系统；4)胶质母细胞瘤免疫微环境对治疗的反应如何？至 为了解决这些问题，我们将使用与人类非常接近的当代小鼠脑胶质瘤模型 和操纵先天免疫系统和获得性免疫系统来剖析其影响和重要性 在抗PD-1治疗的背景下。验证将使用来自人类受试者的数据进行 用抗PD-1治疗。通过阐明抗PD-1治疗活性的机制作用，我们可以识别 能够对这种策略做出反应的胶质母细胞瘤患者的子集。这是一个重要的领域 如果胶质母细胞瘤患者要从免疫治疗中受益，就需要解决未得到满足的需求。这些研究还可能揭示 抗PD-1治疗对先天免疫系统和获得性免疫系统都有双重作用，当一只手臂不是 在操作上，该制剂将其调节特性切换到主要的免疫手臂。

ABSTRACT Immunotherapy has revolutionized cancer treatment by reversing the immune suppression of cytotoxic anti- tumor CD8+ effector T cells. However, glioblastoma patients have profound lymphopenia and immune checkpoint inhibition treatment does not restore T cell immune function. Extensive characterization by our group has demonstrated that glioblastoma is fundamentally different relative to other malignancies in its preferential enrichment of innate immune cells such as macrophages and microglia that are recruited to the tumor microenvironment. These innate immune cells are tumor supportive. In a genetically-engineered mouse model (GEMM) of glioblastoma we recapitulated lympophenia using a CD8 knockout (KO) background, and found marked enrichment of PD-1 expressing macrophages in the murine glioma microenvironment – similar to observations made in human glioblastoma patients. We evaluated the effect of anti-PD-1 Ab delivered intravenously in glioblastoma-bearing wild-type mice and in the CD8 KO background and found therapeutic benefit even in the absence of the CD8 effector T cell. Both peripheral monocyte-derived macrophages and resident microglia were reduced within the glioblastoma microenvironment in mice treated with the anti-PD-1 Ab. As such, our overall study hypothesis is that anti-PD-1 exerts therapeutic immune modulatory effects against glioblastoma through innate immunity in the central nervous system (CNS). This proposal will address multiple crucial questions to the field including: 1) Does the anti-PD-1 Ab cross into the CNS to exert a therapeutic effect; 2) what immune cells, other than the CD8 T cell, are contributing to the therapeutic effect of this agent; 3) are the immune cells that are mediating the therapeutic effect arising from the periphery or are they intrinsic to the CNS; and 4) how does the glioblastoma immune microenvironment change in response to treatment? To address these questions, we will use contemporary murine models of glioma that closely approximate human glioblastoma and manipulate both the innate and adaptive immune systems to dissect the impact and importance of each in the context of anti-PD-1 treatment. Validation will be carried out using data from human subjects treated with anti-PD-1. By clarifying the mechanistic role of anti-PD-1 therapeutic activity, we may identify the subset of glioblastoma patients that are capable of responding to this type of strategy. This is a significant area of unmet need if glioblastoma patients are to benefit from immunotherapy. These studies may also reveal that anti-PD-1 treatment has a dual role on both the innate and adaptive immune system and when one arm is not operational this agent toggles its modulatory properties to the dominant immune arm.