Brain barriers at the crossroads of glioma immune surveillance and immunotherapy response

Abstract

Immunotherapies have substantially advanced cancer treatment; however, their efficacy in gliomas remains limited. This observation cannot be fully explained by tumour-intrinsic factors and may rather be linked to the distinct relationship between the central nervous system (CNS) and the immune system, commonly described as CNS immune privilege. CNS immune privilege is maintained by specialized brain barriers that divide the CNS into compartments with distinct accessibility to immune mediators and immune cells. Although maintaining homeostasis of the CNS parenchyma, these brain barriers direct CNS immune surveillance to the subarachnoid and the perivascular spaces at the CNS borders. Consequently, tumours arising in the CNS parenchyma are shielded from effective immune detection, limiting the efficacy of immunotherapies such as immune checkpoint inhibitors, cancer vaccines and adoptive T cell therapies such as chimeric antigen receptor (CAR) T cells and T cell receptor (TCR) transgenic T cells by restricting their access. Importantly, emerging evidence also indicates that gliomas actively remodel brain barrier functions to reinforce immune evasion. Failure to adequately consider brain barrier function in the context of immunotherapy strategies and clinical trial design therefore represents a major gap in the field. Understanding the orchestrated function of the brain barriers as neuroimmunological interfaces is essential for enhancing immune surveillance and improving immunotherapy responses in patients with brain tumours. Immunotherapy remains largely ineffective in gliomas despite success in other cancers. In this Review, Engelhardt and Platten outline how central nervous system immune privilege is enforced by specialized brain barriers that restrict T cell surveillance and discuss strategies to overcome these barriers to improve T cell-based immunotherapy for glioma.