Laboratory of Molecular Neurobiology, Neurobiology Center, Nencki Institute of Experimental Biology of the Polish Academy of Sciences, Warsaw, Poland.
Lab Invest. 2017 May;97(5):498-518. doi: 10.1038/labinvest.2017.19. Epub 2017 Mar 13.
High-grade gliomas are rapidly progressing tumors of the central nervous system (CNS) with a very poor prognosis despite extensive resection combined with radiation and/or chemotherapy. Histopathological and flow cytometry analyses of human and rodent experimental gliomas revealed heterogeneity of a tumor and its niche, composed of reactive astrocytes, endothelial cells, and numerous immune cells. Infiltrating immune cells consist of CNS resident (microglia) and peripheral macrophages, granulocytes, myeloid-derived suppressor cells (MDSCs), and T lymphocytes. Intratumoral density of glioma-associated microglia/macrophages (GAMs) and MDSCs is the highest in malignant gliomas and inversely correlates with patient survival. Although GAMs have a few innate immune functions intact, their ability to be stimulated via TLRs, secrete cytokines, and upregulate co-stimulatory molecules is not sufficient to initiate antitumor immune responses. Moreover, tumor-reprogrammed GAMs release immunosuppressive cytokines and chemokines shaping antitumor responses. Both GAMs and MDSCs have ability to attract T regulatory lymphocytes to the tumor, but MDSCs inhibit cytotoxic responses mediated by natural killer cells, and block the activation of tumor-reactive CD4 T helper cells and cytotoxic CD8 T cells. The presence of regulatory T cells may further contribute to the lack of effective immune activation against malignant gliomas. We review the immunological aspects of glioma microenvironment, in particular composition and various roles of the immune cells infiltrating malignant human gliomas and experimental rodent gliomas. We describe tumor-derived signals and mechanisms driving myeloid cell accumulation and reprogramming. Although, understanding the complexity of cell-cell interactions in glioma microenvironment is far from being achieved, recent studies demonstrated several glioma-derived factors that trigger migration, accumulation, and reprogramming of immune cells. Identification of these factors may facilitate development of immunotherapy for gliomas as immunomodulatory and immune evasion mechanisms employed by malignant gliomas pose an appalling challenge to brain tumor immunotherapy.
高级别神经胶质瘤是一种中枢神经系统（CNS）快速进展的肿瘤，尽管进行了广泛的切除联合放疗和/或化疗，但其预后仍非常差。对人类和啮齿动物实验性神经胶质瘤的组织病理学和流式细胞术分析表明，肿瘤及其微环境存在异质性，由反应性星形胶质细胞、内皮细胞和大量免疫细胞组成。浸润性免疫细胞包括中枢神经系统固有细胞（小胶质细胞）和外周巨噬细胞、粒细胞、髓源性抑制细胞（MDSCs）和 T 淋巴细胞。脑肿瘤相关小胶质细胞/巨噬细胞（GAMs）和 MDSCs 的肿瘤内密度在恶性神经胶质瘤中最高，并与患者的生存呈反比。尽管 GAMs 具有一些完整的固有免疫功能，但它们通过 TLR 被刺激、分泌细胞因子和上调共刺激分子的能力不足以引发抗肿瘤免疫反应。此外，肿瘤重编程的 GAMs 释放免疫抑制细胞因子和趋化因子，塑造抗肿瘤反应。GAMs 和 MDSCs 都有能力将调节性 T 淋巴细胞吸引到肿瘤中，但 MDSCs 抑制自然杀伤细胞介导的细胞毒性反应，并阻止肿瘤反应性 CD4 T 辅助细胞和细胞毒性 CD8 T 细胞的激活。调节性 T 细胞的存在可能进一步导致针对恶性神经胶质瘤缺乏有效的免疫激活。我们综述了神经胶质瘤微环境的免疫学方面，特别是浸润恶性人类神经胶质瘤和实验性啮齿动物神经胶质瘤的免疫细胞的组成和各种作用。我们描述了肿瘤衍生信号和机制，驱动髓样细胞的积累和重编程。尽管对神经胶质瘤微环境中细胞-细胞相互作用的复杂性的理解还远远没有实现，但最近的研究表明了几种触发免疫细胞迁移、积累和重编程的神经胶质瘤衍生因子。鉴定这些因子可能有助于开发神经胶质瘤的免疫治疗，因为恶性神经胶质瘤所采用的免疫调节和免疫逃逸机制对脑肿瘤免疫治疗构成了严峻的挑战。
