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

Immune Checkpoint in Brain Metastases

From an evolutionary perspective, cancer cells have developed various features to escape immune surveillance. PD-L1 is an immune-checkpoint molecule that regulates immune homeostasis and prevents autoimmunity.[86] In pathological conditions, such as pancreatic cancer, the expression of PD-L1 shields the tumour cells from the activation of cytotoxic T cells.[87] Unlike other immune-surveillance molecules like CTLA4, the expression of PD-1 is not limited to T cells, but occurs in B cells as well.[88] This highlights the wider range of functions exhibited by PD-L1.[89]

It is unclear how metastatic brain cells develop mechanisms to overcome the effect of T cells. Heavy reliance on breaking the interaction between T cells and metastatic brain cancer cells and the ablation of specific metabolic pathways result in activation of pro-survival mechanisms in the cancer cells, presenting a potential therapeutic avenue against lethal advancement. The PD-1 receptor was first identified on thymocytes in response to a pro-apoptotic stimulus. Further studies linked the function of this receptor to immunological tolerance. Like CTLA4, PD-1 belongs to the CD28 family and is known for its inhibitory effect. Upon antigenic stimulation, the tail region of PD-1 is phosphorylated, leading to the recruitment and activation of SHP-2.[90] This is followed by complex formation with SRC-based family receptors, resulting in the activation of ERK and RAS signalling pathways in primary brain tumours.[91] The exact mechanism by which this occurs is still unclear but it seems to be related to the ability of PD-1 to inhibit the production of IFN-induced nitric oxide,[92] suppress glucose metabolism, and inhibit arginine and tryptophan amino acids.[93]

Most recently it was shown that therapeutic reduction of PD-1 expression leads to cytoprotective autophagy induction in tumour cells, thereby increasing their survival. Two PD-1 receptor ligands are known: PD-L1 and PD-L2 belonging to the B7 family.[94,95] PD-1, PD-L1 and PD-L2 were observed to be differentially expressed between primary and metastatic tumours.[95] Further histopathological examination of these immune checkpoints in metastatic lesions revealed that their expression is correlated with shorter overall survival.[95]

The inhibition of PD-1 and CTLA4 on T cells in brain metastases seems to also depend on the status of the systemic disease. In melanoma brain metastases, the efficacy of intracranial immune checkpoint inhibition was observed only when an extracranial tumour was present.[96,97] Extracranial presence further increased the trafficking of CD8+ T cells and TAMs to brain tumours, in response to immune checkpoint therapy. Moreover, tumour-induced peripheral immunosuppression promotes brain metastases in patients with NSCLC. Increased expression of PD-L1 on peripheral TAMs decreases T-cell activation and trafficking, leading to poor outcomes.[98]

Potential mechanisms that limit immune responses to checkpoint inhibitors also include brain access and vascular permeability. Despite being leaky to a variable extent, blood vessels in brain tumour settings are less permeable than in extracranial tumours.[2,11] Anti-PD-1 and anti-CTLA4 blocking antibodies have limited access to intracranial tumours and thus their ability to reduce PD-1 and CTLA4 inhibition of T cells is diminished. Nevertheless, effective immune responses against brain metastatic cells can be dependent on the production of antigen-specific T cells as a result of PD-1 blockade or CTLA4 inhibition in the extracranial tumour site.[97,99] Moreover, tumour antigens of brain metastases may reach draining lymph nodes, leading to the induction of T-cell priming and the release of antigen-specific T cells from checkpoint inhibition in the extracranial tumour-draining lymph nodes.[97]

Brain metastatic cells can be genetically and phenotypically different from their primary tumour origin. Genomic characterization of brain metastases revealed that in 53% of cases, clinically informative alterations in brain metastases were not detected in the matched primary tumour sample.[100] Distal extracranial and regional lymph node metastases were highly divergent from brain metastases, whereby detected alterations associated with sensitivity to PI3K/AKT/mTOR, CDK and HER2/EGFR inhibitors in the brain metastases.[100] These differences between primary and metastatic tumour cells further include alterations in immune responses, inflammation-related pathways, NF-kB1 activity and cytokine profiles.[51] For example, lymphotoxin β expression was directly correlated with M2 polarization of parenchymal macrophages in the setting of brain metastases.[51]

The expression of immune checkpoint molecules in the immune microenvironment of brain metastases can affect the immune modulatory response against tumour cells. Studies exploring PD-1 expression on T cells in the setting of brain metastases showed wide discrepancies in results, with PD-1 expression noted in 3.1–68% of brain metastatic samples.[21,101,102] PD-L1 expression was detected in 25–28% of immune cells in the setting of brain metastatic cells.[101,103,104] On tumour cells, PD-L1 expression ranged from 22% to 75% in brain metastatic samples.[21,101–107]

Therapeutic advancements against metastasis are particularly successful when targeting multiple pathways of the metastatic process. In the clinical setting, therapeutic efficacy and significant prolongation of survival were observed with interventions that simulate anticancer responses mediated by T cells. Ongoing preclinical studies demonstrate survival benefit in models of melanoma, lung and breast cancers upon blockade of interactions between T cells and cancer cells.[108] Nonetheless, the mechanism of interplay remains wide open as clinical translation of such therapies has only been able to demonstrate benefit in melanoma brain metastasis.[23]