Glioblastoma-associated Microglia and Macrophages: Targets for Therapies to Improve Prognosis

Candice C. Poon; Susobhan Sarkar; V. Wee Yong; John J. P. Kelly

Disclosures

Brain. 2017;140(6):1548-1560. 

In This Article

Abstract and Introduction

Abstract

Glioblastoma is the most common and most malignant primary adult human brain tumour. Diagnosis of glioblastoma carries a dismal prognosis. Treatment resistance and tumour recurrence are the result of both cancer cell proliferation and their interaction with the tumour microenvironment. A large proportion of the tumour microenvironment consists of an inflammatory infiltrate predominated by microglia and macrophages, which are thought to be subverted by glioblastoma cells for tumour growth. Thus, glioblastoma-associated microglia and macrophages are logical therapeutic targets. Their emerging roles in glioblastoma progression are reflected in the burgeoning research into therapeutics directed at their modification or elimination. Here, we review the biology of glioblastoma-associated microglia and macrophages, and model systems used to study these cells in vitro and in vivo. We discuss translation of results using these model systems and review recent advances in immunotherapies targeting microglia and macrophages in glioblastoma. Significant challenges remain but medications that affect glioblastoma-associated microglia and macrophages hold considerable promise to improve the prognosis for patients with this disease.

Introduction

Glioblastoma comprises the majority of malignant primary adult brain tumours (Ostrom et al., 2014) and has one of the worst survival rates of all cancers (Scott et al., 1999; Krex et al., 2007). The poor prognosis is a product of the transformed cells acting in collusion with a tumour microenvironment (Charles et al., 2012; Zhou and Bao, 2014; Hambardzumyan and Bergers, 2015; Quail et al., 2016) comprised in large part of vascular and stromal cells together with inflammatory infiltrates (Rossi et al., 1987; Hewedi et al., 2013). Glioblastoma-associated microglia and macrophages (GAMMs) predominate this immune infiltrate (Morantz et al., 1979), making them important considerations for tumour biology and therapy. These innate immune cells are meant to participate in tumour surveillance and eradication, but they become compromised by glioblastoma and exploited in the process. In this review, we discuss the evidence demonstrating that GAMMs are subverted in glioblastoma. We consider the use and limitations of glioblastoma models, the strategies developed to modify or ablate GAMMs, and the translatability of these approaches to treat the human condition.

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