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IL-33 increases ST2+ Tregs and promotes metastatic tumour growth in the lungs in an amphiregulin-dependent manner.

Abstract：

:Regulatory T cells (Tregs) facilitate primary and metastatic tumour growth through the suppression of anti-tumour immunity. Emerging evidence suggests a distinct role for Tregs in mediating tissue repair and barrier integrity in the lungs by IL-33 mediated production of the growth factor amphiregulin (AREG). Dependent on the type of cancer and local microenvironment, AREG may induce tumour cell proliferation, invasion, migration or resistance to apoptosis by signaling through the epidermal growth factor receptor (EGFR). We have found that IL-33 is dramatically increased in and around metastatic tumour foci in the lungs of mice bearing orthotopic murine mammary tumours. We observed that Tregs express significantly more of the IL-33 receptor, ST2, relative to conventional T cells, that ST2+ Tregs accumulate in the lungs of metastatic tumour-bearing mice, and that ST2+ Tregs produce significantly more AREG than ST2- Tregs. The intranasal administration of recombinant IL-33 increased the proportion of AREG producing ST2+ Tregs and enhanced the level of phosphorylated EGFR in the metastatic lungs. While recombinant AREG did not impact mammary tumour cell proliferation in vitro despite inducing a dose-dependent increase in phosphorylated EGFR, intranasal administration of AREG resulted in a ten-fold increase in pulmonary metastatic tumour burden in vivo. Further, the intranasal administration of recombinant IL-33 significantly increased metastatic tumour burden in the lungs in an amphiregulin-dependent manner. These data identify ST2+ Tregs as a microenvironmental source of AREG in the lungs of mice with orthotopic metastatic mammary tumours and highlight an important role for AREG in promoting metastatic tumour growth in the lungs.

journal_name

Oncoimmunology

journal_title

Oncoimmunology

authors

Halvorsen EC,Franks SE,Wadsworth BJ,Harbourne BT,Cederberg RA,Steer CA,Martinez-Gonzalez I,Calder J,Lockwood WW,Bennewith KL

doi

10.1080/2162402X.2018.1527497

subject

Has Abstract

pub_date

2018-10-16 00:00:00

pages

e1527497

issue

eissn

2162-4011

issn

2162-402X

pii

1527497

journal_volume

pub_type

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IL-33 increases ST2+ Tregs and promotes metastatic tumour growth in the lungs in an amphiregulin-dependent manner.