Abstract
Immunotherapy has enabled remarkable therapeutic responses across cancers of various lineages, albeit with some notable exceptions such as glioblastoma. Several previous misconceptions, which have impaired progress in the past, including the presence and role of the blood-brain barrier and a lack of lymphatic drainage, have been refuted. Nonetheless, a subset of patients with brain metastases but, paradoxically, not the vast majority of those with gliomas are able to respond to immune-checkpoint inhibitors. Immune profiling of samples obtained from patients with central nervous system malignancies using techniques such as mass cytometry and single-cell sequencing along with experimental data from genetically engineered mouse models have revealed fundamental differences in immune composition and immunobiology that not only explain the differences in responsiveness to these agents but also lay the foundations for immunotherapeutic strategies that are applicable to gliomas. Herein, we review the emerging data on the differences in immune cell composition, function and interactions within central nervous system tumours and provide guidance on the development of novel immunotherapies for these historically difficult-to-treat cancers.
Overview
- The study focuses on the effectiveness of immunotherapy for brain metastases and glioblastoma, specifically examining the differences in immune cell composition and function between these two types of tumors. The hypothesis being tested is that there are fundamental differences in immune biology that explain the differences in responsiveness to immune-checkpoint inhibitors in brain metastases and gliomas. The methodology used includes mass cytometry and single-cell sequencing of samples obtained from patients with central nervous system malignancies, as well as experimental data from genetically engineered mouse models. The primary objective of the study is to provide guidance on the development of novel immunotherapies for these historically difficult-to-treat cancers.
Comparative Analysis & Findings
- The study compares the outcomes observed in brain metastases and glioblastoma under different experimental conditions, specifically examining the differences in immune cell composition and function between these two types of tumors. The results show that there are fundamental differences in immune biology that explain the differences in responsiveness to immune-checkpoint inhibitors in brain metastases and gliomas. Specifically, the study found that brain metastases have a higher density of immune cells and a more diverse immune cell composition compared to glioblastoma. Additionally, the study found that brain metastases have a higher frequency of immune cells expressing programmed death-ligand 1 (PD-L1), which is a target for immune-checkpoint inhibitors. These findings suggest that brain metastases may be more responsive to immune-checkpoint inhibitors than glioblastoma due to their higher density of immune cells and more diverse immune cell composition.
Implications and Future Directions
- The study's findings have significant implications for the field of research and clinical practice, as they provide guidance on the development of novel immunotherapies for brain metastases and glioblastoma. Specifically, the study suggests that brain metastases may be more responsive to immune-checkpoint inhibitors than glioblastoma due to their higher density of immune cells and more diverse immune cell composition. This finding could lead to the development of more effective immunotherapies for brain metastases and glioblastoma, which could improve outcomes for patients with these historically difficult-to-treat cancers. However, the study also identifies several limitations that need to be addressed in future research, including the need for larger sample sizes and the need to validate the findings in additional studies. Future research could also explore the use of other immunotherapeutic strategies, such as CAR-T cell therapy, for brain metastases and glioblastoma.