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Review ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Immunol. | doi: 10.3389/fimmu.2019.01713

Microenvironmental regulation of tumor progression and therapeutic response in brain metastasis

  • 1Institute for Tumor Biology and Experimental Therapy, Georg Speyer Haus, Germany
  • 2Faculty of Biological Sciences, Goethe University Frankfurt am Main, Germany
  • 3Goethe University, Frankfurt Cancer Institute (FCI), Germany
  • 4German Cancer Consortium, German Cancer Research Center (DKFZ), Germany

Cellular and non-cellular components of the tumor microenvironment (TME) are emerging as key regulators of primary tumor progression, organ-specific metastasis and therapeutic response. In the era of TME-targeted- and immunotherapies, cancer-associated inflammation has gained increasing attention. In this regard, the brain represents a unique and highly specialized organ. It has long been regarded as an immunological sanctuary site where the presence of the blood brain barrier (BBB) and blood cerebrospinal fluid barrier (BCB) restricts the entry of immune cells from the periphery. Consequently, tumor cells that metastasize to the brain were thought to be shielded from systemic immune surveillance and destruction. However, the detailed characterization of the immune landscape within border-associated areas of the central nervous system (CNS), such as the meninges and the choroid plexus, as well as the discovery of lymphatics and channels that connect the CNS with the periphery, have recently challenged the dogma of the immune privileged status of the brain. Moreover, the presence of brain metastases (BrM) disrupts the integrity of the BBB and BCB. Indeed, BrM induce the recruitment of different immune cells from the myeloid and lymphoid lineage to the CNS. Blood-borne immune cells together with brain-resident cell-types, such as astrocytes, microglia and neurons, form a highly complex and dynamic TME that affects tumor cell survival and modulates the mode of immune responses that are elicited by brain metastatic tumor cells. In this review, we will summarize recent findings on heterotypic interactions within the brain metastatic TME and highlight specific functions of brain-resident and recruited cells at different rate-limiting steps of the metastatic cascade. Based on the insight from recent studies, we will discuss new opportunities and challenges for TME-targeted and immunotherapies for BrM.

Keywords: brain metastases, Tumor microenviroment, Microglia, Astrocytes, Immune System, Immunotherapy, Neurons

Received: 15 May 2019; Accepted: 09 Jul 2019.

Edited by:

Leila Akkari, The Netherlands Cancer Institute (NKI), Netherlands

Reviewed by:

William K. Decker, Baylor College of Medicine, United States
Egídio Torrado, University of Minho, Portugal  

Copyright: © 2019 Schulz, Salamero-Boix, Niesel, Alekseeva and Sevenich. 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. Lisa Sevenich, Georg Speyer Haus, Institute for Tumor Biology and Experimental Therapy, Frankfurt am Main, 60596, Germany,