T Cell Dysfunction in Glioblastoma: a Barrier and an Opportunity for the Development of Successful Immunotherapies

Purpose Of Review: Immunotherapies such as immune checkpoint blockade have revolutionized cancer treatment, but current approaches have failed to improve outcomes in glioblastoma and other brain tumours. T cell dysfunction has emerged as one of the major barriers for the development of central nervous system (CNS)-directed immunotherapy. Here, we explore the unique requirements that T cells must fulfil to ensure immune surveillance in the CNS, and we analyse T cell dysfunction in glioblastoma (GBM) through the prism of CNS-resident immune responses.

Recent Findings: Using comprehensive and unbiased techniques such as single-cell RNA sequencing, multiple studies have dissected the transcriptional state of CNS-resident T cells that patrol the homeostatic brain. A similar approach has revealed that in GBM, tumour-infiltrating T cells lack the hallmarks of antigen-driven exhaustion typical of melanoma and other solid tumours, suggesting the need for better presentation of tumour-derived antigens. Consistently, in a mouse model of GBM, increasing lymphatic drainage to the cervical lymph node was sufficient to promote tumour rejection.

Summary: For the success of future immunotherapy strategies, further work needs to explore the natural history of dysfunction in GBM tumour-infiltrating T cells, establish whether these originate from CNS-resident T cells and how they can be manipulated therapeutically.