Glioma-derived IL-33 orchestrates an inflammatory brain tumor microenvironment that accelerates glioma progression.

Abstract

Despite a deeper molecular understanding, human glioblastoma remains one of the most treatment refractory and fatal cancers. It is known that the presence of macrophages and microglia impact glioblastoma tumorigenesis and prevent durable response. Herein we identify the dual function cytokine IL-33 as an orchestrator of the glioblastoma microenvironment that contributes to tumorigenesis. We find that IL-33 expression in a large subset of human glioma specimens and murine models correlates with increased tumor-associated macrophages/monocytes/microglia. In addition, nuclear and secreted functions of IL-33 regulate chemokines that collectively recruit and activate circulating and resident innate immune cells creating a pro-tumorigenic environment. Conversely, loss of nuclear IL-33 cripples recruitment, dramatically suppresses glioma growth, and increases survival. Our data supports the paradigm that recruitment and activation of immune cells, when instructed appropriately, offer a therapeutic strategy that switches the focus from the cancer cell alone to one that includes the normal host environment.

• Authors: Astrid De Boeck, Bo Young Ahn, Charlotte D'Mello, Xueqing Lun, Shyam V Menon, Mana M Alshehri, Frank Szulzewsky, Yaoqing Shen, Lubaba Khan, Ngoc Ha Dang, Elliott Reichardt, Kimberly-Ann Goring, Jennifer King, Cameron J Grisdale, Natalie Grinshtein, Dolores Hambardzumyan, Karlyne M Reilly, Michael D Blough, J Gregory Cairncross, V Wee Yong, Marco A Marra, Steven J M Jones, David R Kaplan, Kathy D McCoy, Eric C Holland, Pinaki Bose, Jennifer A Chan, Stephen M Robbins, Donna L Senger
• Journal: Nature communications (Nat Commun) Vol. 11 Issue 1 Pg. 4997 (10 05 2020) ISSN: 2041-1723 [Electronic] England
• PMID: 33020472 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cytokines
• IL33 protein, human
• Interleukin-33

Topics

• Animals
• Brain Neoplasms (metabolism, mortality, pathology)
• Carcinogenesis
• Cell Nucleus (metabolism)
• Cytokines (metabolism)
• Glioblastoma (metabolism, mortality, pathology)
• Glioma (metabolism, mortality, pathology)
• Humans
• Inflammation
• Interleukin-33 (metabolism)
• Killer Cells, Natural (metabolism, pathology)
• Macrophages (metabolism, pathology)
• Mice
• Mice, SCID
• Microglia
• Survival Analysis
• T-Lymphocytes (metabolism, pathology)
• Tumor Microenvironment (immunology)