Targeting Tumor Associated Macrophages to Overcome Conventional Treatment Resistance in Glioblastoma

Abstract

Glioblastoma (GB) is the most common and devastating form of brain cancer. Despite conventional treatments, progression or recurrences are systematic. In recent years, immunotherapies have emerged as an effective treatment in a number of cancers, leaving the question of their usefulness also faced with the particular case of brain tumors. The challenge here is major not only because the brain is the seat of our consciousness but also because of its isolation by the blood-brain barrier and the presence of a unique microenvironment that constitutes the central nervous system (CNS) with very specific constituent or patrolling cells. Much of the microenvironment is made up of immune cells or inflammation. Among these, tumor-associated macrophages (TAMs) are of significant interest as they are often involved in facilitating tumor progression as well as the development of resistance to standard therapies. In this review, the ubiquity of TAMs in GB will be discussed while the specific case of microglia resident in the brain will be also emphasized. In addition, the roles of TAMs as accomplices in the progression of GB and resistance to treatment will be presented. Finally, clinical trials targeting TAMs as a means of treating cancer will be discussed.

Keywords: crosstalks; glioblastoma; macrophages; microglia; radiation; resistance; tumor-associated macrophage.

Figure 1

Tumor-associated macrophage activities in glioblastoma progression. This figure shows the pro-tumoral (angiogenesis, invasion, proliferation and immunosuppressive properties) and anti-tumor (Tumor cell killing, Th1 response and anti-tumor activity) activities of tumor-associated macrophages (TAMs) in brain tumors. (1) Monocytes are recruited to the tumor where they differentiate into macrophages. The tumor is involved in their programming as it sends different signals to induce a specific phenotype in favor of the tumor. (2) TAMs that are recruited can either polarize into a continuum of macrophage states that are described with two extremes: an M1 (2a) or an M2 (2b) phenotype depending on the signal they receive (IFNγ/LPS/GM-CSF for M1 and IL-4/IL-13/M-CSF for M2) Pyonteck et al., 2013; Kast et al., 2017; Roesch et al., 2018. (3) M1-like TAMs are macrophages with anti-tumor properties such as tumor cell kill abilities mediated by the production of NO, ROS, IFNγ Kennedy et al., 2013; Leblond et al., 2017. They also mediate the Th1 response in the tumor through the activation of Th helper cells by secreting CXCL9, CXCL10, IL-12 Poon et al., 2017. Finally, they also display an anti-tumor activity by activating cytotoxic T cells via TNFα and IL1β. (4) M2-like TAMs have pro tumoral properties such as enhancing the invasive and proliferative ability of GB cells by secreting CSF-1, MMPs, Pyk2, TGFβIIR, TGFβ, IL-6, IL-10, and EGF. They can also mediate the immunosuppressive environment through the expression of IL-6, MIC-1, MIF, STAT3, and TGFβ. Finally, TAMs also regulate angiogenesis through the following factors: IL-6, MIC-1, MIF, STAT3, and TGFβ. (5) The tumor controls the polarization of TAMs through the production of soluble factors (CCL2/CCL7/SDF-1/CX3CL1/VEGF/POSTN/Ecrg4) Feng et al., 2015; Hambardzumyan et al., 2015; Lee et al., 2015; Zhou et al., 2015; Chang et al., 2016; Chen and Hambardzumyan, 2018; Turkowski et al., 2018 and microvesicle factors (EGFRvIII, miR451, miR21) Van Der Vos et al., 2016; Manda et al., 2018. (6) The tumor is also able to send signals to recruit new peripherical macrophages. (7) Environmental cues including radiotherapy, chemotherapy, O₂ level, pH are involved in the programing and functions of macrophages Hardee et al., 2012. (8) Healthy brain cells and TAMs probably interact and are involved in the programming of TAMs. Their interaction has yet to be studied. CCL2, C-C motif chemokine ligand 2; CCL7, C-C motif chemokine ligand 7; CSF-1, colony stimulating factor 1; CXCL2, C-X3-C motif chemokine ligand 2; CX3CL1, C-X3- C motif chemokine ligand 1; Ecrg4, esophageal cancer-related gene 4; EGF, endothelial growth fact; IGFBP1, insulin-like growth factor-binding protein 1; IL-1β, interleukin-1 beta; IL-10, interleukin-10; IL-6, interleukin-6; MIC-1, macrophage inhibitory cytokine 1; MIF, macrophage migration inhibitory factor; MMPs, matrix metalloproteinases; POSTN, periostin; Pyk2, proline rich tyrosine kinase 2; SDF-1, stromal cell-derived factor 1; STAT3, signal transducer and activator of transcription3; TGF-β, transforming growth factor-beta; TGFβIIR, TGF-beta type II receptor; VEGF, vascular endothelial growth factor; βFGF, basic fibroblast growth factor.