Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, Frankfurt, Germany.
Biological Sciences, Faculty 15, Goethe University, Frankfurt, Germany.
Front Immunol. 2019 Jul 24;10:1713. doi: 10.3389/fimmu.2019.01713. eCollection 2019.
Cellular and non-cellular components of the tumor microenvironment (TME) are emerging as key regulators of primary tumor progression, organ-specific metastasis, and therapeutic response. In the era of TME-targeted- and immunotherapies, cancer-associated inflammation has gained increasing attention. In this regard, the brain represents a unique and highly specialized organ. It has long been regarded as an immunological sanctuary site where the presence of the blood brain barrier (BBB) and blood cerebrospinal fluid barrier (BCB) restricts the entry of immune cells from the periphery. Consequently, tumor cells that metastasize to the brain were thought to be shielded from systemic immune surveillance and destruction. However, the detailed characterization of the immune landscape within border-associated areas of the central nervous system (CNS), such as the meninges and the choroid plexus, as well as the discovery of lymphatics and channels that connect the CNS with the periphery, have recently challenged the dogma of the immune privileged status of the brain. Moreover, the presence of brain metastases (BrM) disrupts the integrity of the BBB and BCB. Indeed, BrM induce the recruitment of different immune cells from the myeloid and lymphoid lineage to the CNS. Blood-borne immune cells together with brain-resident cell-types, such as astrocytes, microglia, and neurons, form a highly complex and dynamic TME that affects tumor cell survival and modulates the mode of immune responses that are elicited by brain metastatic tumor cells. In this review, we will summarize recent findings on heterotypic interactions within the brain metastatic TME and highlight specific functions of brain-resident and recruited cells at different rate-limiting steps of the metastatic cascade. Based on the insight from recent studies, we will discuss new opportunities and challenges for TME-targeted and immunotherapies for BrM.
肿瘤微环境（TME）的细胞和非细胞成分正在成为调节原发性肿瘤进展、器官特异性转移和治疗反应的关键因素。在 TME 靶向治疗和免疫治疗时代，癌症相关炎症受到了越来越多的关注。在这方面，大脑是一个独特而高度专业化的器官。长期以来，人们一直认为大脑是一个免疫豁免部位，血脑屏障（BBB）和血脑脊液屏障（BCB）的存在限制了外周免疫细胞的进入。因此，转移到大脑的肿瘤细胞被认为免受全身免疫监视和破坏。然而，中枢神经系统（CNS）边界相关区域（如脑膜和脉络丛）内免疫景观的详细特征，以及发现与外周连接的淋巴管和通道，最近对大脑免疫特权地位的教条提出了挑战。此外，脑转移瘤（BrM）的存在破坏了 BBB 和 BCB 的完整性。事实上，BrM 从髓系和淋巴系募集不同的免疫细胞到中枢神经系统。血液来源的免疫细胞与脑驻留细胞类型（如星形胶质细胞、小胶质细胞和神经元）一起形成一个高度复杂和动态的 TME，影响肿瘤细胞的存活，并调节由脑转移瘤细胞引发的免疫反应模式。在这篇综述中，我们将总结最近关于脑转移瘤 TME 中异质相互作用的发现，并强调脑驻留细胞和募集细胞在转移级联的不同限速步骤中的特定功能。基于最近研究的见解，我们将讨论针对 BrM 的 TME 靶向治疗和免疫治疗的新机会和挑战。
