Dynamics of glioma-associated microglia and macrophages reveals their divergent roles in the immune response of brain

Abstract

Glioma microenvironment contains numerous myeloid cells, including brain-resident microglia and recruited monocytes and macrophages (Mo/Mφ). When studied collectively, these cells presented pro-tumor effects. Yet, little is known about the differences among these myeloid populations. Using single-cell sequencing analysis, we studied the phenotypic characteristics, spatial variances, and dynamic changes of these relatively heterogeneous cell populations. Microglia populations with distinct spatial distribution presented different functional states, including tumor-associated subsets with phagocytic and lipid metabolism signature. Notably, this subset of glioma-associated microglia shared similar trait in a diverse spectrum of neuropathogenesis. In contrast, Mo/Mφ highly expressed genes related to angiogenesis, tumor invasion, and immune evasion. Moreover, identifying the Mo/Mφ subsets had prognostic and classificatory value in clinical application. These results thus eliminate the long-existing ambiguity about the role of microglia and Mo/Mφ in glioma pathogenesis, and reveal their prognostic and therapeutic value for glioma patients.

The Oncogenesis of Glial Cells in Diffuse Gliomas and Clinical Opportunities

“…2). Nevertheless, Qian et al found that Crybb1 and Ldhb are specific and stable markers across different tumor stages in mice, and the cluster of MDMs consistently featured with Iqgap1 corresponded to other clinical datasets [80]. A variety of cytokines (IL-6 and IL-10) and several genes encoding chemokines associated with wound healing (Ccl22, Ccl17, Cxcl2, and Cxcl3) are upregulated in TAMs [81].…”

Brain macrophage development, diversity and dysregulation in health and disease

“…Altered expression of these widely used microglial markers was subsequently observed during the course of CNS diseases. P2RY12 serves as a prototypical example of altered microglial markers during brain disorders, and a decrease in its expression is a prominent feature of microglia in Alzheimer’s disease [ 137 ] and glioma [ 138 ]. Other markers for microglia in homeostatic conditions, such as Cx3cr1 , Sall1 , and Tmem119 , are also downregulated in glioma [ 138 ].…”

“…P2RY12 serves as a prototypical example of altered microglial markers during brain disorders, and a decrease in its expression is a prominent feature of microglia in Alzheimer’s disease [ 137 ] and glioma [ 138 ]. Other markers for microglia in homeostatic conditions, such as Cx3cr1 , Sall1 , and Tmem119 , are also downregulated in glioma [ 138 ]. Despite some incremental progress, a lack of widely accepted cell markers limits the functional confirmation of these two cell populations.…”

“…data). Using RNAscope, we found that these cells are mainly located at the tumor periphery and infiltrate into the superficial area of the tumor lesion [ 138 ](Qian J, 2021, unpubl. data).…”