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

Jie Li, Megan M. Kaneda, Jun Ma, Ming Li, Ryan M. Shepard, Kunal Patel, Tomoyuki Koga, Aaron Sarver, Frank Furnari, Beibei Xu, Sanjay Dhawan, Jianfang Ning, Hua Zhu, Anhua Wu, Gan You, Tao Jiang, Andrew S. Venteicher, Jeremy N. Rich, Christopher K. Glass, Judith A. VarnerClark C. Chen

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

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.

Original languageEnglish (US)
Article numbere2009290118
JournalProceedings of the National Academy of Sciences of the United States of America
Volume118
Issue number16
DOIs
StatePublished - Apr 20 2021

Bibliographical note

Funding Information:
Wellcome Fund Career Awards for Medical Scientists (https://www.bwfund. org/), the Kimmel Scholar award (http://www.kimmel.org), and a Discovery Grant from the American Brain Tumor Association (https://www.abta.org/). We thank Dr. Bing Ren for his helpful comments. We are grateful to Brian Hirshman, Valya Ramakrishnan, Florina Grigore, Mihir Gupta, and Johnny Akers for assistance in qRT-PCR, informatics analysis, animal care, and graphical design.

Funding Information:
ACKNOWLEDGMENTS. The work is supported by NIH grants NS097649-01 and CA240953-01, the Doris Duke Charitable Foundation Clinical Scientist Development award (https://www.ddcf.org/), the Sontag Foundation Distinguished Scientist Award (http://www.sontagfoundation.org), the Burroughs

Funding Information:
The work is supported by NIH grants NS097649-01 and CA240953-01, the Doris Duke Charitable Foundation Clinical Scientist Development award (https://www.ddcf.org/), the Sontag Foundation Distinguished Scientist Award (http://www.sontagfoundation.org), the Burroughs Wellcome Fund Career Awards for Medical Scientists (https://www.bwfund. org/), the Kimmel Scholar award (http://www.kimmel.org), and a Discovery Grant from the American Brain Tumor Association (https://www.abta.org/). We thank Dr. Bing Ren for his helpful comments. We are grateful to Brian Hirshman, Valya Ramakrishnan, Florina Grigore, Mihir Gupta, and Johnny Akers for assistance in qRT-PCR, informatics analysis, animal care, and graphical design.

Publisher Copyright:
© 2021 National Academy of Sciences. All rights reserved.

Keywords

  • Exceptional responders
  • Glioblastoma
  • IL11
  • Microglia/macrophages
  • PI3Kγ

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