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

Yolanda Pires-Afonso,Simone P Niclou,Alessandro Michelucci

doi:10.3390/ijms21030689

Yolanda Pires-Afonso, Simone P Niclou + Show 1 more

Open Access

https://doi.org/10.3390/ijms21030689

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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.

Highlights

Gliomas represent approximately 80% of all malignant tumours of the central nervous system (CNS) [1]
Tumour-associated microglia/macrophages (TAMs), which can constitute up to 30–40% of the bulk tumour mass, outnumber by far infiltrating lymphocytes in these tumours [3]. This scarcity of lymphocytes in the tumour microenvironment contrasts with other tumour types, e.g., melanoma or lung cancer, classifying GBM as immunologically ‘cold tumours’
Microglia and macrophages in GBM are educated by the tumour and display unique molecular prooggrraammss,whwichhiclhargelalyrgderliyve tdurmivoeur-tsuumppoourt-isvueppphoerntiovteypepsh. eHnoowtyepveesr., thHe oavwaeilvaebrl,e suthbepopauvlaaitliaobnles asunbdpfoupnuctlaiotinosnosf athnedsefucnelcltsioanlosnogfGtBheMsedecevlelslopalmonegntGanBdMprdoegvreelsospiomneanrte aonndlyppraorgtiraelslsyiounndaerrestoonoldy

Summary

Introduction

Gliomas represent approximately 80% of all malignant tumours of the central nervous system (CNS) [1]. Whether or not these tumours are intrinsically non-immunogenic or whether lymphocytes, including T cells, are actively excluded, remains to be determined [5] In this context, an extensive immunogenomic analysis of more than 10,000 tumours comprising data from 33 diverse cancer types compiled by The Cancer Genome Atlas (TCGA) allowed to identify six different immune subtypes: wound healing, IFN-γ dominant, inflammatory, lymphocyte depleted, immunologically quiet and TGF-β dominant [6]. Future studies should investigate the link between specific genomic alterations and their contribution to the adaptation of the tumour microenvironment As expected, in this classification GBMs were among the “lymphocyte depleted” subtype displaying a prominent macrophage signature, with Th1 suppressed and high M2 response [6]. We will pinpoint the aspects linked to their diversity that warrant further investigations and how this heterogeneity may be harnessed for the development of novel personalized immune therapeutic strategies

M1 and M2 Polarization States

Glioblastoma Subtyping and Single-Cell Analyses

Single-Cell Analyses of Microglia and Macrophages in Glioblastoma

Findings

Conclusions and Perspectives