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PI3Kγ inhibition suppresses microglia/TAM accumulation in glioblastoma microenvironment to promote exceptional
Jie Li1, Megan M Kaneda2, Jun Ma1
1Department of Neurosurgery, University of Minnesota, Minneapolis, MN 55455.
Abstract:
Precision medicine in oncology leverages clinical observations of exceptional response. Toward an understanding of the molecular features that define this response, we applied an integrated, multiplatform analysis of RNA profiles derived from clinically annotated glioblastoma samples. This analysis suggested that specimens from exceptional responders are characterized by decreased accumulation of microglia/macrophages in the glioblastoma microenvironment. Glioblastoma-associated microglia/macrophages secreted interleukin 11 (IL11) to activate STAT3-MYC signaling in glioblastoma cells. This signaling induced stem cell states that confer enhanced tumorigenicity and resistance to the standard-of-care chemotherapy, temozolomide (TMZ). Targeting a myeloid cell restricted an isoform of phosphoinositide-3-kinase, phosphoinositide-3-kinase gamma isoform (PI3Kγ), by pharmacologic inhibition or genetic inactivation disrupted this signaling axis by reducing microglia/macrophage-associated IL11 secretion in the tumor microenvironment. Mirroring the clinical outcomes of exceptional responders, PI3Kγ inhibition synergistically enhanced the anti-neoplastic effects of TMZ in orthotopic murine glioblastoma models. Moreover, inhibition or genetic inactivation of PI3Kγ in murine glioblastoma models recapitulated expression profiles observed in clinical specimens isolated from exceptional responders. Our results suggest key contributions from tumor-associated microglia/macrophages in exceptional responses and highlight the translational potential for PI3Kγ inhibition as a glioblastoma therapy.
Insights
Targeting microglia/macrophages in glioblastoma can improve treatment response. Inhibiting phosphoinositide-3-kinase gamma (PI3Kγ) reduces tumor-promoting signals, enhancing chemotherapy effectiveness.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Precision medicine in oncology relies on understanding exceptional treatment responses.
- Glioblastoma (GBM) presents a significant therapeutic challenge, necessitating novel treatment strategies.
Purpose of the Study:
- To elucidate the molecular mechanisms underlying exceptional responses in glioblastoma.
- To identify potential therapeutic targets for improving glioblastoma treatment outcomes.
Main Methods:
- Integrated, multiplatform RNA profiling of clinically annotated glioblastoma samples.
- Analysis of microglia/macrophage function and signaling pathways within the glioblastoma microenvironment.
- Pharmacologic and genetic inhibition of phosphoinositide-3-kinase gamma (PI3Kγ) in preclinical glioblastoma models.
Main Results:
- Exceptional responders showed reduced microglia/macrophage accumulation in the tumor microenvironment.
- Glioblastoma-associated microglia/macrophages secrete interleukin 11 (IL11), activating STAT3-MYC signaling and promoting stem cell states resistant to temozolomide (TMZ).
- PI3Kγ inhibition disrupted this IL11-mediated signaling, synergistically enhanced TMZ efficacy in murine models, and recapitulated exceptional responder profiles.
Conclusions:
- Tumor-associated microglia/macrophages play a critical role in glioblastoma exceptional responses.
- Targeting PI3Kγ offers a promising therapeutic strategy to overcome treatment resistance and improve glioblastoma patient outcomes.
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