PI3Kγ inhibition suppresses microglia/TAM accumulation in glioblastoma microenvironment to promote exceptional temozolomide response.

Autor:	Li J; Department of Neurosurgery, University of Minnesota, Minneapolis, MN 55455., Kaneda MM; Moores Cancer Center, University of California San Diego, La Jolla, CA 92037., Ma J; Department of Neurosurgery, University of Minnesota, Minneapolis, MN 55455., Li M; Department of Neurosurgery, University of Minnesota, Minneapolis, MN 55455., Shepard RM; Moores Cancer Center, University of California San Diego, La Jolla, CA 92037., Patel K; Department of Neurosurgery, University of California, Los Angeles, CA 90095., Koga T; Department of Neurosurgery, University of Minnesota, Minneapolis, MN 55455., Sarver A; Institute for Health Informatics, University of Minnesota, Minneapolis, MN 55455., Furnari F; Ludwig Institute for Cancer Research, University of California San Diego, La Jolla, CA., Xu B; Department of Neurosurgery, University of Minnesota, Minneapolis, MN 55455., Dhawan S; Department of Neurosurgery, University of Minnesota, Minneapolis, MN 55455., Ning J; Department of Neurosurgery, University of Minnesota, Minneapolis, MN 55455., Zhu H; Department of Neurosurgery, University of Minnesota, Minneapolis, MN 55455.; Department of Pediatrics, The First Hospital of China Medical University, Shenyang 110122, China., Wu A; Department of Neurosurgery, The First Hospital of China Medical University, Shenyang 110122, China., You G; Department of Neurosurgery, University of Minnesota, Minneapolis, MN 55455.; Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China., Jiang T; Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China.; Department of Molecular Neuropathology, Beijing Neurosurgical Institute, Capital Medical University, Beijing 100050, China., Venteicher AS; Department of Neurosurgery, University of Minnesota, Minneapolis, MN 55455., Rich JN; Department of Medicine, Division of Regenerative Medicine, University of California San Diego, La Jolla, CA 92093., Glass CK; Department of Medicine, University of California San Diego, La Jolla, CA 92093., Varner JA; Department of Pathology, University of California San Diego, La Jolla, CA 92161., Chen CC; Department of Neurosurgery, University of Minnesota, Minneapolis, MN 55455; ccchen@umn.edu.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2021 Apr 20; Vol. 118 (16).
DOI:	10.1073/pnas.2009290118
Abstrakt:	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. Competing Interests: The authors declare no competing interest.
Databáze:	MEDLINE
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