Faculty, Staff and Student Publications
Publication Date
10-1-2024
Journal
Journal of Clinical Investigation
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.
Keywords
Glioblastoma, Animals, PTEN Phosphohydrolase, Mice, Microglia, Humans, Protein-Lysine 6-Oxidase, Brain Neoplasms, Macrophages, Tumor Microenvironment, Cell Line, Tumor, Neoplasm Proteins, Signal Transduction
DOI
10.1172/JCI178628
PMID
39352749
PMCID
PMC11563674
PubMedCentral® Posted Date
10-1-2024
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes
Included in
Bioinformatics Commons, Biomedical Informatics Commons, Genetic Phenomena Commons, Medical Genetics Commons, Oncology Commons