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


The brain continues to be a special organ in terms of immune regulation, with the blood–brain barrier being a major contributor to this immune state. The immunosuppressive role of the tumour microenvironment in the setting of brain metastases emphasizes the need for new therapeutic strategies that can reverse immunosuppression. These strategies should aim to favour the M1 state of macrophages or help in the recruitment of cytotoxic T cells. They can also target immunosuppressive elements like regulatory T cells and TAMs. So far, immunotherapy has failed to show significant benefit in breast cancer brain metastases (unlike in metastatic melanoma and NSCLC). As such, approaches that aim to flip cold brain metastatic tumours to hot ones should be emphasized and the potential risk of inducing autoimmunity should be evaluated. It is also important to consider that immunosuppression is a protective mechanism that keeps the brain safe from excessive inflammation and subsequent oedema that may harm the sensitive structures of the brain, leading to damage. Understanding the biological underpinnings and detailed mechanisms that are implicated in immunosuppression of brain metastases is vital to design novel immune interventions that are safe, efficacious and can elicit an enduring response. Embracing combination therapy with immune checkpoint inhibitors seems to yield better clinical outcomes and survival benefit. As such, strategies that are based on the biological mechanisms of these inhibitors should be adopted. Developing appropriate preclinical models that recapitulate the immune microenvironment in the setting of brain metastases is a necessity for the advancement of novel therapies that can be translated to clinical practice.