# Lack of ST2 aggravates glioma invasiveness, vascular abnormality, and immune suppression

## TL;DR

This study shows that the absence of the ST2 receptor in mice leads to more aggressive gliomas, worse survival, and a more immunosuppressive tumor environment.

## Contribution

The novel finding is that ST2 deficiency in the tumor microenvironment promotes glioma invasiveness, vascular changes, and immune suppression.

## Key findings

- ST2-deficient mice develop more invasive gliomas with increased extracellular matrix remodeling and angiogenesis.
- Lack of ST2 correlates with a more immunosuppressive tumor environment.
- IL-33 is primarily produced by oligodendrocytes surrounding the tumor.

## Abstract

Glioblastoma (GBM) is the most common primary malignant brain tumor in adults, characterized by aggressive growth and a dismal prognosis. Interleukin-33 (IL-33) and its receptor ST2 have emerged as regulators of glioma growth, but their exact function in tumorigenesis has not been deciphered. Indeed, previous studies on IL-33 in cancer have yielded somewhat opposing results as to whether it is pro- or anti-tumorigenic.

IL-33 expression was assessed in a GBM tissue microarray and public databases. As in vivo models we used orthotopic xenografts of patient-derived GBM cells, and syngenic models with grafted mouse glioma cells.

We analyzed the role of IL-33 and its receptor ST2 in nonmalignant cells of the glioma microenvironment and found that IL-33 levels are increased in cells surrounding the tumor. Protein complexes of IL-33 and ST2 are mainly found outside of the tumor core. The IL-33-producing cells consist primarily of oligodendrocytes. To determine the function of IL-33 in the tumor microenvironment, we used mice lacking the ST2 receptor. When glioma cells were grafted to ST2-deficient mouse brains, the resulting tumors exhibited a more invasive growth pattern, and are associated with poorer survival, compared to wild-type mice. Tumors in ST2-deficient hosts are more invasive, with increased expression of extracellular matrix remodeling enzymes and enhanced tumor angiogenesis. Furthermore, the absence of ST2 leads to a more immunosuppressive environment.

Our findings reveal that glia-derived IL-33 and its receptor ST2 participate in modulating tumor invasiveness, tumor vasculature, and immunosuppression in glioma.