Musatova Oxana, Kumar Vikas, Vinogradov Konstantin, Rubtsov Yury
Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Science, Moscow, Russia.
Department of Bioinformatics and Systems Biology, Phystech School of Biological and Medical Physics, Moscow Institute of Physics and Technology, Dolgoprudny, Moscow Region, Russia.
Front Immunol. 2025 Aug 15;16:1639521. doi: 10.3389/fimmu.2025.1639521. eCollection 2025.
Gliomas are aggressive brain tumors of glial origin accounting for about 80% of the central nervous system (CNS) malignancies. Glioma cells are known to form a highly immunosuppressive tumor microenvironment (TME) capable of inhibiting T cell activation and protecting tumors from elimination by the immune system. One of the predominant immune inhibitory mechanisms in the TME are immune checkpoints: a complex system of membrane-bound ligands on tumor and immune cells that interact with surface receptors on T lymphocytes and affect their activation and cytotoxicity. There is mounting evidence regarding the role of immune checkpoints expressed in gliomas, in particular, their most aggressive form - glioblastoma multiforme (GBM). In this review, we discuss the immune checkpoints with proven expression in gliomas, their ligands, related signaling pathways, co-expression profiles, and the effects of immune cells on antitumor activity. We collected data not only on the canonical immune checkpoints (e.g. PD-1/PD-L1 or CTLA-4) but also on novel and alternative ones including soluble mediators and enzymes. We review data describing the correlation of immune checkpoint expression with patient survival as well as co-expression with other molecules involved in glioma development. Where possible, we analyzed the differences between immune checkpoints in low-grade (LGG) and high-grade gliomas (HGG). Negative effects of several immune checkpoints on T cells could be eliminated by therapeutic monoclonal antibodies that block the interaction between checkpoint ligands and receptors. Therefore, alongside with traditional approaches and T cell-based immunotherapy, the antibody-mediated blockade of immune checkpoints could be considered as a potentially promising therapeutic approach against gliomas.
神经胶质瘤是起源于神经胶质细胞的侵袭性脑肿瘤，约占中枢神经系统（CNS）恶性肿瘤的80%。已知胶质瘤细胞会形成高度免疫抑制的肿瘤微环境（TME），能够抑制T细胞活化并保护肿瘤免受免疫系统清除。TME中主要的免疫抑制机制之一是免疫检查点：肿瘤细胞和免疫细胞上的膜结合配体组成的复杂系统，其与T淋巴细胞表面受体相互作用并影响其活化和细胞毒性。越来越多的证据表明神经胶质瘤中表达的免疫检查点的作用，特别是其最具侵袭性的形式——多形性胶质母细胞瘤（GBM）。在本综述中，我们讨论了在神经胶质瘤中已证实表达的免疫检查点、其配体、相关信号通路、共表达谱以及免疫细胞对抗肿瘤活性的影响。我们不仅收集了关于经典免疫检查点（如PD-1/PD-L1或CTLA-4）的数据，还收集了包括可溶性介质和酶在内的新型和替代性免疫检查点的数据。我们综述了描述免疫检查点表达与患者生存率以及与神经胶质瘤发生过程中涉及的其他分子共表达之间相关性的数据。在可能的情况下，我们分析了低级别（LGG）和高级别神经胶质瘤（HGG）中免疫检查点之间的差异。几种免疫检查点对T细胞的负面影响可通过阻断检查点配体与受体之间相互作用的治疗性单克隆抗体消除。因此，除了传统方法和基于T细胞的免疫疗法外，抗体介导的免疫检查点阻断可被视为一种潜在的有前景的神经胶质瘤治疗方法。
