Abstract
Glioblastoma is the most common and aggressive brain tumor, which is uniformly lethal due to its extreme invasiveness and the absence of curative therapies. Immune checkpoint inhibitors have not yet proven efficacious for glioblastoma patients, due in part to the low prevalence of tumor-reactive T cells within the tumor microenvironment. The priming of tumor antigen-directed T cells in the cervical lymph nodes is complicated by the shortage of dendritic cells and lack of appropriate lymphatic vessels within the brain parenchyma. However, recent data suggest that naive T cells may also be primed within brain tumor-associated tertiary lymphoid structures. Here, we review the current understanding of the formation of these structures within the central nervous system, and hypothesize that promotion of tertiary lymphoid structures could enhance priming of tumor antigen-targeted T cells and sensitize glioblastomas to cancer immunotherapy.
Highlights
Glioblastoma (GBM) is a grade IV astrocytoma with dismal prognosis
We briefly summarize the current understanding of the immunosuppressive GBM microenvironment, the formation and function of tertiary lymphoid structures (TLS) in the central nervous system (CNS), and the putative implications for GBM immunity and immunotherapy
In GBM, the inflammatory milieu compromises the integrity of the blood-brain barrier (BBB) [25] but the vasculature is highly abnormal, which is in part due to pro-angiogenic factors such as vascular endothelial growth factor (VEGF) in the tumor microenvironment (TME) [26, 27]
Summary
Glioblastoma (GBM) is a grade IV astrocytoma with dismal prognosis. The overall survival is only 12-15 months despite conventional therapy, which includes maximal surgical resection, adjuvant temozolomide chemotherapy and radiotherapy [1]. The lack of response in GBM is likely due to the scarcity of tumor antigen-directed T cells within the tumor microenvironment (TME). Brain tumor immunity and the response to ICI can be improved through ectopic expression of vascular endothelial growth factor (VEGF)-C, which enhances lymphangiogenesis in the dura mater and thereby antigen transport to cervical lymph nodes in mouse models of glioma [9, 10]. T cells primed against tumor-associated antigens travel through the blood circulation and extravasate into the TME via activated tumor vasculature [11]. This process, referred to as the cancer-immunity cycle, is less efficient in the central nervous system (CNS) than in the periphery. We briefly summarize the current understanding of the immunosuppressive GBM microenvironment, the formation and function of TLS in the CNS, and the putative implications for GBM immunity and immunotherapy
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