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. 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.

Automated summary

Purpose of review: Immunotherapies, such as immune checkpoint blockade, have greatly impacted cancer treatment, but have not been as successful in improving outcomes for glioblastoma and other brain tumors. T cell dysfunction is a major barrier in the development of CNS-directed immunotherapy. Recent studies using advanced techniques such as single-cell RNA sequencing have provided insights into the transcriptional state of CNS-resident T cells and revealed differences in T cell function in glioblastoma compared to other solid tumors. Further research is needed to understand the dysfunction of tumor-infiltrating T cells in glioblastoma and explore therapeutic manipulation options.