Abstract
Brain metastases are common intracranial neoplasms and their frequency increases with prolonged survival of cancer patients. New pharmaceuticals targeting oncogenic kinases and immune checkpoint inhibitors augment both overall and progression-free survival in patients with brain metastases, but are not fully successful in reducing metastatic burden and still a majority of oncologic patients die due to dissemination of the disease. Despite therapy advancements, median survival of patients with brain metastases is several months, although it may vary in different types or subtypes of cancer. Contribution of the innate immune system to cancer progression is well established. Tumor-associated macrophages (TAMs), instead of launching antitumor responses, promote extracellular matrix degradation, secrete immunosuppressive cytokines, promote neoangiogenesis and tumor growth. While their roles as pro-tumorigenic cells facilitating tissue remodeling, invasion and metastasis is well documented, much less is known about the immune microenvironment of brain metastases and roles of specific immune cells in those processes. The central nervous system (CNS) is armed in resident myeloid cells: microglia and perivascular macrophages which colonize CNS in early development and maintain homeostasis in brain parenchyma and at brain-blood vessels interfaces. In this study we discuss available data on the immune composition of most common brain metastases, focusing on interactions between metastatic cancer cells and microglia, perivascular and meningeal macrophages. Cancer cells ‘highjack’ several CNS protective mechanisms and may employ microglia and CNS-border associated macrophages into helping cancer cells to colonize a pre-metastatic niche. We describe emerging molecular insights into mechanisms governing communication between microglia and metastatic cancer cells that culminate in activation of CNS resident microglia and trafficking of monocytic cells from the periphery. We present mechanisms controlling those processes in brain metastases and hypothesize on potential therapeutic approaches. In summary, microglia and non-parenchymal brain macrophages are involved in multiple stages of a metastatic disease and, unlike tumor cells, are genetically stable and predictable, which makes them an attractive target for anticancer therapies.
Highlights
Cancer develops in a complex tissue microenvironment and nonmalignant cells of a tumor microenvironment (TME) display tumor-promoting activities at many stages of cancer promotion and progression [1]
Several studies reported the accumulation of HLA-DR+ microglia/macrophages in the intracranial metastatic lesions in breast, melanoma, small cell lung, and non-small cell lung cancers [45], but understanding which roles they play in metastatic seeding of central nervous system (CNS) and lesion progression escaped prior notice
The first study assessing the phenotypes of myeloid cells was performed with a small Primary central nervous system lymphoma (PCNSL) cohort (n = 43), and numbers of CD68+, CD163+, and CD204+ Tumor-associated macrophages (TAMs) were not associated with prognosis of patients [96]
Summary
Cancer develops in a complex tissue microenvironment and nonmalignant cells of a tumor microenvironment (TME) display tumor-promoting activities at many stages of cancer promotion and progression [1]. Mutual communication between cancer cells and cellular components of microenvironment maintain normal tissue homeostasis, and supports tumor growth. This intercellular communication is operated by a multifaceted and dynamic network of cytokines, chemokines, growth factors, and enzymes remodeling extracellular matrix, leading to profound changes in properties of the surrounding tissue. Immune cells are polarized into proinvasive, immunosuppressive cells supporting tumor progression [1, 2]. Central nervous system (CNS) metastases, with incidence of 8.3 to 14.3 per 100,000 people [6], are recognized as the most common intracranial neoplasms Their frequency increases with expanding life expectancy and prolonged survival of cancer patients. Median survival of patients with brain metastases remains 6 months [7]
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