IL33 Orchestrates the Brain Tumor Microenvironment to Promote Glioma Progression

Student Researcher:
Astrid De Boeck

Supervisor / Principle Investigator:
Dr. Stephen Robbins

Additional Authors:
Astrid De Boeck
Xueqing Lun
Bo Young Ahn
Yoaqing Shen
Mana Alshehri
Ngoc Ha Dang
Xiuling Wang
Kimberly-Ann Goring
Jennifer King
Marco A. Marra
Steven JM Jones
J. Gregory Cairncross
V. Wee Yong
Jennifer Chan
Donna L. Senger
Stephen M. Robbins

MD Class of 2022

ABSTRACT

Despite a deeper understanding of human glioblastoma (GBM) there has been minimal improvement in patient survival. Macrophage infiltration is a common feature of GBM and an inverse correlation between tumor-associated macrophage infiltration and prognosis has been reported. Using genetically and phenotypically diverse patient-derived Brain Tumour Initiating Cell (BTIC) intracranial mouse models we identified a number of secreted factors within the inflammatory GBM microenvironment. Here we focused on the role of IL33, a recently identified member of the IL-1 cytokine family that has both secreted and nuclear functions and acts on a wide range of innate and adaptive immune cells. We found that IL33 is expressed in a subset of primary GBM specimens and that ectopic expression of IL33 significantly enhanced tumor progression through secreted and nuclear functions. Secreted IL33 mediates the recruitment and activation of macrophages whereas nuclear IL33 regulates the glioma-derived expression of inflammatory cytokines that provides a favourable microenvironment for tumor progression. This study provides the first evidence that IL33 is a major orchestrator of the GBM microenvironment. Altering therapeutic emphasis from the cancer cell to one of altering or co-targeting the host environment provides a paradigm shift for therapeutic treatment of patients with GBM.

 
 

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