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Front. Mol. Neurosci. | doi: 10.3389/fnmol.2019.00282

Immune checkpoint blockade – how does it work in brain metastases?

  • 1University of Leeds, United Kingdom
  • 2Leeds Teaching Hospitals NHS Trust, United Kingdom

Immune checkpoints restrain the immune system following its activation and their inhibition unleashes anti-tumor immune responses. Immune checkpoint inhibitors revolutionized the treatment of several cancer types, including melanoma, and immune checkpoint blockade with anti-PD-1 and anti-CTLA-4 antibodies is becoming a frontline therapy in metastatic melanoma. Notably, up to 60% of metastatic melanoma patients develop metastases in the brain. Brain metastases are also very common in patients with lung and breast cancer, and occur in ~20-40% of patients across different cancer types. Metastases in the brain are associated with poor prognosis due to the lack of efficient therapies. In the past, patients with brain metastases used to be excluded from immune-based clinical trials due to the assumption that such therapies may not work in the context of “immune-specialized” environment in the brain, or may cause harm. However, recent trials in patients with brain metastases demonstrated safety and intracranial activity of anti-PD-1 and anti-CTLA-4 therapy. We here discuss how immune checkpoint therapy works in brain metastases, with focus on T cells and the cross-talk between brain metastases, the immune system, and tumors growing outside the brain. We discuss major open questions in our understanding of what is required for an effective immune checkpoint inhibitor therapy in brain metastases.

Keywords: Extracranial tumor, immune checkpoints, immune response, Immunotherapy, brain metastases

Received: 26 Apr 2019; Accepted: 05 Nov 2019.

Copyright: © 2019 Lorger, Andreou, Fife and James. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Mihaela Lorger, University of Leeds, Leeds, United Kingdom,