Macrophages in Glioblastoma

Glioblastoma (GBM) is one of the most aggressive tumors in humans. Despite multimodal therapeutic interventions, the median survival of GBM patients is still restricted to about 15 months. One of the main reasons for the observed treatment resistance and concomitant tumor recurrence is the invasive growth of GBM preventing a total tumor resection as well as profound changes in the tumor microenvironment. The immune system plays a significant role in the development of GBM, particularly tumor-associated macrophages (TAMs). The function of TAMs on tumor cells is dependent on their type of activation. The reprogrammed M1-TAMs suppress the growth of GBM cells meanwhile the M2 macrophages are described to favor tumor development and resistance to therapy. Therefore, modulating the exchange between those two cell populations may be therapeutically relevant.

Macrophages States

TAMs that are recruited can either polarize into a continuum of macrophage states that are described with two extremes: an M1 or an M2 phenotype depending on the signal they receive. M1-like TAMs are macrophages with anti-tumor properties such as tumor cell killing abilities mediated by the production of NO, reactive oxygen species (ROS), interferon γ (IFNγ). They also mediate the T-helper 1 response in the tumor through the activation of T-helper cells by secreting C-X-C motif chemokine ligand 9 (CXCL9), CXCL10, interleukin 12 (IL-12). Finally, they also display an anti-tumor activity by activating cytotoxic T cells via tumor necrosis factor (TNFα) and IL1β. M2-like TAMs have pro tumoral properties such as enhancing the invasive and proliferative ability of GBM cells by secreting colony-stimulating factor (CSF-1), matrix metalloproteinases (MMPs), proline-rich tyrosine kinase 2 (Pyk2), transforming growth factorβ (TGFβ), TGFβIIR, IL-6, IL-10, and epidermal growth factor (EGF). They can also mediate the immunosuppressive environment through the expression of IL-6, macrophage inhibitory cytokine 1 (MIC-1), migration inhibitory factor (MIF), signal transducer and activator of transcription 3 (STAT3), and TGFβ. Finally, TAMs also regulate angiogenesis through the following factors: IL-6, MIC-1, MIF, STAT3, and TGFβ. The tumor controls the polarization of TAMs through the production of soluble factors (chemokine ligand 2 (CCL2)/CCL7/SDF1/CX3CL1/vascular endothelial growth factor (VEGF)) and microvesicle factors (EGFRvIII, miR451, miR21).

Fig.1 TAMs activities in GBM progression. (Grégoire, 2020)

TAMs and Clinical Therapeutics

• Surgical Resection: Surgical resection is the current standard treatment for GBM. TAMs enhance the stemness and chemo radioresistance in GBM cells. It was shown that tumor phenotypes associated with telomerase overexpression and TAMs infiltration were more complicated to resect.
• Radiotherapy: Macrophages inside the tumor mass are involved in multiple phenomena that include radiation resistance. TAMs participate in the induction of GBM cell differentiation to a mesenchymal state through NF-kB production, an event that correlated with radiation resistance.
• Chemotherapy: Temozolomide (TMZ) is commonly used to treat GBM. TAMs that express CD74 were described to be involved in TMZ resistance by inducing AKT (also named protein kinase B, PKB) and extracellular regulated protein kinases 1/2 (ERK1/2) activation in tumor cells.

Clinical Implications of TAMs in GBM

The presence of TAMs has already been well described in GBM. The number of TAMs and their activation status may affect GBM prognosis. Further research indicated that human GBM shows a mixed population of M1/M2 TAMs. M2 TAMs were related to an adverse prognostic of GBM. Moreover, research derived from magnetic resonance imaging in GBM indicated that extremely aggressive tumors were also related to TAMs. Based on these findings, TAMs are crucial for the progression of GBM, and evaluating them may give us more information on the GBM prognosis.

TAM-targeted Therapeutics in GBM

There are several strategies of therapies targeting TAMs:

• Targeting TAMs to block their recruitment to the tumor site. It can be achieved by targeting the CCL2/chemokine receptor 2 (CCR2) axis. CCL2 is an inflammatory chemokine that can recruit macrophages and Treg lymphocytes leading to an immunosuppressive environment.
• Reprogramming of TAMs toward an antitumoral phenotype: 1) Inhibition of CD47: CD47 expressed by cancer cells inhibits phagocytosis through its interaction with signal regulatory protein-a (SIRPa) expressed by macrophages thus sending out a "do not eat me" signal; 2) Activation of CD40: CD40 is expressed on monocytes, macrophages, dendritic cells, and B cells and belongs to the TNF receptor superfamily. Targeting CD40 modulated the immune cell number and led to an antitumor response; 3) Toll-like receptors (TLRs) Agonist: TLRs are normally activated by microbial moieties (including nucleic acids) allowing macrophages to acquire an M1 phenotype.
• Depletion of TAMs. The activation of TAMs is dependent on the CSF1R signaling pathway. Against CSF1R signaling pathway and bisphosphonates are two ways to deplete the number of TAMs in the tumor.

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References

1. Gregoire, H.; et al. Targeting tumor-associated macrophages to overcome conventional treatment resistance in glioblastoma. Front Pharmacol. 2020, 11:368.
2. Poon, C.C.; et al. Glioblastoma-associated microglia and macrophages: targets for therapies to improve prognosis. Brain. 2017, 140(6):1548-1560.