Proceedings of the National Academy of Sciences - PNAS, 2021-04, Vol.118 (16), p.1
2021
Details
- Autor(en) / Beteiligte
- Titel
- PI3Kγ inhibition suppresses microglia/TAM accumulation in glioblastoma microenvironment to promote exceptional temozolomide response
- Ist Teil von
- Proceedings of the National Academy of Sciences - PNAS, 2021-04, Vol.118 (16), p.1
- Ort / Verlag
- United States: National Academy of Sciences
- Erscheinungsjahr
- 2021
- Link zum Volltext
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- 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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0027-8424eISSN: 1091-6490DOI: 10.1073/pnas.2009290118Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_8072253
- Format
- –
- Schlagworte
- Accumulation, Adult, Animal models, Animals, Biological Sciences, Brain Neoplasms - pathology, Cell Line, Tumor, Chemotherapy, Class Ib Phosphatidylinositol 3-Kinase - metabolism, Deactivation, Drug Resistance, Neoplasm - physiology, Female, Glioblastoma, Glioblastoma - drug therapy, Glioblastoma - metabolism, Glioblastoma - pathology, Glioblastoma cells, Humans, Inactivation, Interleukin 1, Interleukin 11, Interleukin-11 - immunology, Interleukin-11 - metabolism, Kinases, Macrophages, Male, Mice, Mice, Inbred C57BL, Mice, Nude, Microglia, Microglia - metabolism, Microglia - physiology, Myc protein, Phosphatidylinositol 3-Kinase - metabolism, Phosphoinositide-3 Kinase Inhibitors - pharmacology, Precision medicine, Signal Transduction - drug effects, Signaling, Stat3 protein, Stem cells, Temozolomide, Temozolomide - metabolism, Temozolomide - pharmacology, Tumor microenvironment, Tumor Microenvironment - drug effects, Tumor-Associated Macrophages - metabolism, Tumor-Associated Macrophages - physiology, Tumorigenicity, Tumors