Dual targeting macrophages and microglia is a therapeutic vulnerability in models of PTEN-deficient glioblastoma
Yang Liu1,2, Junyan Wu1, Hinda Najem1
1Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.
Abstract:
Tumor-associated macrophages and microglia (TAMs) are critical for tumor progression and therapy resistance in glioblastoma (GBM), a type of incurable brain cancer. We previously identified lysyl oxidase (LOX) and olfactomedin like-3 (OLFML3) as essential macrophage and microglia chemokines, respectively, in GBM. Here, single-cell transcriptomics and multiplex sequential immunofluorescence followed by functional studies demonstrate that macrophages negatively correlate with microglia in the GBM tumor microenvironment. LOX inhibition in PTEN-deficient GBM cells upregulates OLFML3 expression via the NF-κB-PATZ1 signaling pathway, inducing a compensatory increase of microglia infiltration. Dual targeting macrophages and microglia via inhibition of LOX and the CLOCK-OLFML3 axis generates potent antitumor effects and offers a complete tumor regression in more than 60% of animals when combined with anti-PD1 therapy in PTEN-deficient GBM mouse models. Thus, our findings provide a translational triple therapeutic strategy for this lethal disease.
Insights
Targeting lysyl oxidase (LOX) and olfactomedin like-3 (OLFML3) in glioblastoma (GBM) reprogrammed the tumor microenvironment, leading to significant tumor regression when combined with anti-PD1 therapy.
Area of Science:
- Neuro-oncology
- Cancer immunology
- Molecular biology
Background:
- Tumor-associated macrophages and microglia (TAMs) drive glioblastoma (GBM) progression and treatment resistance.
- Lysyl oxidase (LOX) and olfactomedin like-3 (OLFML3) were previously identified as key chemokines for macrophages and microglia in GBM, respectively.
Purpose of the Study:
- To investigate the interplay between macrophages and microglia in the GBM tumor microenvironment.
- To explore the therapeutic potential of targeting LOX and OLFML3 signaling pathways in GBM.
Main Methods:
- Single-cell transcriptomics and multiplex sequential immunofluorescence were employed.
- Functional studies were conducted in PTEN-deficient GBM mouse models.
- Inhibition of LOX and the CLOCK-OLFML3 axis was investigated.
Main Results:
- Macrophages and microglia exhibit a negative correlation within the GBM tumor microenvironment.
- LOX inhibition in PTEN-deficient GBM cells upregulates OLFML3 via NF-κB-PATZ1 signaling, increasing microglia infiltration.
- Dual targeting of LOX and the CLOCK-OLFML3 axis, combined with anti-PD1 therapy, achieved complete tumor regression in over 60% of animals.
Conclusions:
- A novel translational triple therapeutic strategy targeting macrophages, microglia, and the immune checkpoint in GBM.
- This approach demonstrates significant potential for treating glioblastoma, a lethal brain cancer.
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