Revealing and Harnessing Tumour-Associated Microglia/Macrophage Heterogeneity in Glioblastoma

Abstract

Cancer heterogeneity and progression are subject to complex interactions between neoplastic cells and their microenvironment, including the immune system. Although glioblastomas (GBMs) are classified as ‘cold tumours’ with very little lymphocyte infiltration, they can contain up to 30–40% of tumour-associated macrophages, reported to contribute to a supportive microenvironment that facilitates tumour proliferation, survival and migration. In GBM, tumour-associated macrophages comprise either resident parenchymal microglia, perivascular macrophages or peripheral monocyte-derived cells. They are recruited by GBMs and in turn release growth factors and cytokines that affect the tumour. Notably, tumour-associated microglia/macrophages (TAMs) acquire different expression programs, which shape the tumour microenvironment and contribute to GBM molecular subtyping. Further, emerging evidence highlights that TAM programs may adapt to specific tumour features and landscapes. Here, we review key evidence describing TAM transcriptional and functional heterogeneity in GBM. We propose that unravelling the intricate complexity and diversity of the myeloid compartment as well as understanding how different TAM subsets may affect tumour progression will possibly pave the way to new immune therapeutic avenues for GBM patients.

New hints towards a precision medicine strategy for IDH wild-type glioblastoma

“…It is noteworthy that in GBM the previous dual categorisation into M1proinflammatory and M2-immunosuppressive macrophage phenotype has proven to be over-simplistic and does not provide a comprehensive representation of the complex activation states observed. 28 The degree to which macrophages infiltrate the tumour has been shown to correlate with a more aggressive clinical course and reduced OS. 29 Chen et al 30 showed that macrophage-low patients (n ¼ 130) display a greater OS compared with macrophage-high IDH-wt patients (n ¼ 201).…”

“…33,34 Nevertheless, efforts to reprogramme TAMs may prove important for eliciting response to immune therapeutics in a subset of GBM patients. 28 In particular, mesenchymal GBM has been shown to exhibit highest TAM infiltration, 35,36 with significant macrophage content a histological signature of the subtype. Thus, notwithstanding the lack of overall clinical benefit observed to date, TAMs may yet represent a rational target in the mesenchymal setting.…”

Distinct regional ontogeny and activation of tumor associated macrophages in human glioblastoma

“…Therefore, lymphoid cells are not considered in this paper and immune cell are taken to be macrophages. It is known that GBM is relatively lymphodepleted compared to other cancers, making this approximation more feasible 27 . Full details of tumour collection, RNA-sequencing, and quality control parameters can be found in the original paper.…”

Primary and recurrent glioma patient-derived orthotopic xenografts (PDOX) represent relevant patient avatars for precision medicine

“…While the adaptive immune system is largely absent in these mice, they retain a largely functional innate immune system, including microglia, the brain resident immune effector cells, and peripheral myeloid cells. GBM are largely lymphocyte depleted tumors 89 , while microglia and macrophages constitute the major immune component 90 . Here we show that classical glioma TME components such as microglia/macrophages, astrocytes and OPCs are present in xenografted tumors, indicating that tumor cell interactions with the TME remain active in PDOX.…”