Emerging Principles of Brain Immunology and Immune Checkpoint Blockade in Brain Metastases

Jawad Fares; Ilya Ulasov; Peter Timashev; Maciej S. Lesniak


Brain. 2021;144(4):1046-1066. 

In This Article

Abstract and Introduction


Brain metastases are the most common type of brain tumours, harbouring an immune microenvironment that can in principle be targeted via immunotherapy. Elucidating some of the immunological intricacies of brain metastases has opened a therapeutic window to explore the potential of immune checkpoint inhibitors in this globally lethal disease. Multiple lines of evidence suggest that tumour cells hijack the immune regulatory mechanisms in the brain for the benefit of their own survival and progression. Nonetheless, the role of the immune checkpoint in the complex interplays between cancers cells and T cells and in conferring resistance to therapy remains under investigation. Meanwhile, early phase trials with immune checkpoint inhibitors have reported clinical benefit in patients with brain metastases from melanoma and non-small cell lung cancer. In this review, we explore the workings of the immune system in the brain, the immunology of brain metastases, and the current status of immune checkpoint inhibitors in the treatment of brain metastases.


Brain metastases are known to possess extraordinary intratumoural heterogeneity and special features that allow them to impede immunotherapy. Brain immunology, specifically, is governed by a set of doctrines that are different from the immune system elsewhere.[1] The blood–brain barrier plays an important role in dictating the entry of immune agents into the brain, leading to an immunosuppressive environment within the brain parenchyma.[2] As such, metastatic tumours are offered a safe haven in the brain, which makes them a major threat and an important target for therapeutic advancement.

In general, the brain boasts an immunosuppressive environment that does not permit the trafficking of immune cells. Discoveries in the past decade have shown that a special lymphatic system exists to drain from the dura mater of the brain to the peripheral lymph nodes.[3–7] It was further emphasized that endothelial, epithelial and glial brain barriers possess varied accessibility to different immune-cell subtypes.[8] New evidence continues to reveal a role for immune cells in the tumour microenvironment.[1] These results have debunked the widely held belief that the brain is an immune-privileged organ, which is free from immune activity. In fact, antigens derived from the brain are capable of inducing an immune reaction in cervical lymph nodes.[6,7,9,10] In addition, this heterogeneous blood–tumour barrier permeability in the setting of brain metastasis can facilitate the infiltration of multiple immune cells from the peripheral circulation.[11,12]

As our acumen on the immunology of brain metastases continues to grow, we learn that the CNS is home to a variety of antigen-presenting cells (APCs) such as microglia, dendritic cells and macrophages, as well as astrocytes.[8,13] T cells are now known to roam freely in the brain. Yet, this does not take away from the uniqueness of the brain immune system, as it continues to be more limited than the immune system in peripheral organs.

Brain metastatic cells are famous for their ability to manipulate immune responses.[14] While this ability might be helpful in limiting destructive inflammation, it can limit the access of T cells among others. This helps brain metastases escape antitumour immune responses,[15,16] promoting metastatic survival and chemoresistance. The large populations of microglia and monocytes in the brain further contribute to decreasing cell-mediated immunity,[17–19] leaving metastatic progression unchecked.

Reports in the literature continue to emphasize that the factors that contribute to immunosuppression at the primary tumour site are similar to those that contribute to it in the brain, highlighting the role of regulatory T cells and the expression of immune checkpoint programmed cell death 1–ligand 1 (PD-L1),[20,21] which is associated with T cell futility.[16,22] Nevertheless, recent trials with immune checkpoint inhibitors have shown survival and antitumour benefit in patients with melanoma brain metastases.[23]

With the brain as a common site of residence for metastatic cancerous and noncancerous cells, interactions between these cellular components seem inevitable. In this review, we explore the intricacies of the immune microenvironment of brain metastases and the efficacy of immune checkpoint inhibitors in the treatment of secondary tumours in the brain.