Dynamic changes in glioma macrophage populations after radiotherapy reveal CSF-1R inhibition as a strategy to overcome resistance

Abstract

Tumor-associated macrophages (TAMs) and microglia (MG) are potent regulators of glioma development and progression. However, the dynamic alterations of distinct TAM populations during the course of therapeutic intervention, response, and recurrence have not yet been fully explored. Here, we investigated how radiotherapy changes the relative abundance and phenotypes of brain-resident MG and peripherally recruited monocyte-derived macrophages (MDMs) in glioblastoma. We identified radiation-specific, stage-dependent MG and MDM gene expression signatures in murine gliomas and confirmed altered expression of several genes and proteins in recurrent human glioblastoma. We found that targeting these TAM populations using a colony-stimulating factor–1 receptor (CSF-1R) inhibitor combined with radiotherapy substantially enhanced survival in preclinical models. Our findings reveal the dynamics and plasticity of distinct macrophage populations in the irradiated tumor microenvironment, which has translational relevance for enhancing the efficacy of standard-of-care treatment in gliomas.

Single-cell map of diverse immune phenotypes in the acute myeloid leukemia microenvironment

“…CX3CR1 and CSF1R are highly expressed in FCGR3A + (CD16 + ) subset, which can be identified as an inflammatory phenotype in anti-tumor immune response [ 59 ]. Although in preclinical models of glioblastoma, targeting TAMs and microglia using CSF1R inhibitor combined with radiotherapy could enhance survival [ 60 ], might be not suitable for AML patients and impairs anti-tumor immune response [ 61 ]. This reminds us CSF1R inhibitors (such as BLZ945 and PLX3397) might not bring benefit to some AML patients (AML210A, AML329, and AML707B) without identifying major groups of CSF1R-expressing immune cells.…”

Interactions between Tumor Cells, Neurons, and Microglia in the Glioma Microenvironment

“…Once entrenched in the glioma microenvironment, these tumor-educated macrophages would support angiogenesis [12,13,75,84,85], a finding strengthened by the fact that they form physical contacts with blood vessels to a greater degree than microglia [75]. Additional work has revealed that the macrophage proportion increases in recurrent gliomas, potentially suggesting a macrophage functional role in mediating glioma recurrence after radiation [14]. While considerable work still needs to be done to uncover additional roles of these myeloid cells and to pave the way for tumor-specific therapy, mounting evidence seems to suggest specific and distinct roles for microglia and macrophages dependent on their localization within and around a tumor.…”

“…In lieu of pharmacological microglial activation, whole-brain radiation may also be used to induce microglia activation in an effort to promote synaptic pruning [61]. Unfortunately, it also appears that microglia are responsible for radiation-induced cognitive deficits and that elimination of microglia or CSF1R blockade reduces cognitive impairment and boosts radiation efficacy [14,16,[61][62][63]. Thus, while radiation may be used as a tool to study the effect of microglia on NGS, radiation will most likely not produce robust synaptic pruning once this treatment is paired with CSF1R antagonists in a clinical setting.…”

“…CSF1R blockade on myeloid cells repolarized them and diminished their tumor-promoting activity in vivo [10], though this strategy failed to yield significant clinical benefits in the setting of recurrent glioma [98]. CSF1R antagonism may augment radiation efficacy in the pre-clinical [14,16] and clinical setting [99].…”

“…Mounting literature demonstrates that gliomas utilize various mechanisms to subvert multiple cell types in the CNS to fuel their growth and disease progression, including neurons [5][6][7], astrocytes [8], oligodendrocyte precursor cells (OPCs) [9], and the myeloid cell populations macrophages and microglia [9][10][11]. Elegant studies point to the possibility that curbing oncogenic interactions between glioma cells and these cell types could slow tumor progression [6,7,10,12,13] and, in some cases, may sensitize gliomas to the standard of care therapies [14][15][16]. Targeting tumor cell-specific interactions with non-malignant cells engulfed in a rapidly expanding tumor or on the border of a tumor has the potential to curb disease progression while producing minimal off-target toxicities.…”