PMID- 30713780 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20210112 IS - 2162-4011 (Print) IS - 2162-402X (Electronic) IS - 2162-4011 (Linking) VI - 8 IP - 2 DP - 2019 TI - IL-33 increases ST2(+) Tregs and promotes metastatic tumour growth in the lungs in an amphiregulin-dependent manner. PG - e1527497 LID - 10.1080/2162402X.2018.1527497 [doi] LID - e1527497 AB - 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. FAU - Halvorsen, E C AU - Halvorsen EC AD - Integrative Oncology Department, BC Cancer, Vancouver, BC, Canada. AD - Interdisciplinary Oncology Program, University of British Columbia, Vancouver, BC, Canada. FAU - Franks, S E AU - Franks SE AD - Integrative Oncology Department, BC Cancer, Vancouver, BC, Canada. FAU - Wadsworth, B J AU - Wadsworth BJ AD - Integrative Oncology Department, BC Cancer, Vancouver, BC, Canada. AD - Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada. FAU - Harbourne, B T AU - Harbourne BT AUID- ORCID: 0000-0002-6517-9991 AD - Integrative Oncology Department, BC Cancer, Vancouver, BC, Canada. FAU - Cederberg, R A AU - Cederberg RA AD - Integrative Oncology Department, BC Cancer, Vancouver, BC, Canada. AD - Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada. FAU - Steer, C A AU - Steer CA AD - Interdisciplinary Oncology Program, University of British Columbia, Vancouver, BC, Canada. AD - Terry Fox Laboratory, BC Cancer, Vancouver, BC, Canada. FAU - Martinez-Gonzalez, I AU - Martinez-Gonzalez I AD - Terry Fox Laboratory, BC Cancer, Vancouver, BC, Canada. FAU - Calder, J AU - Calder J AD - Integrative Oncology Department, BC Cancer, Vancouver, BC, Canada. AD - Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada. FAU - Lockwood, W W AU - Lockwood WW AD - Integrative Oncology Department, BC Cancer, Vancouver, BC, Canada. AD - Interdisciplinary Oncology Program, University of British Columbia, Vancouver, BC, Canada. AD - Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada. FAU - Bennewith, K L AU - Bennewith KL AD - Integrative Oncology Department, BC Cancer, Vancouver, BC, Canada. AD - Interdisciplinary Oncology Program, University of British Columbia, Vancouver, BC, Canada. AD - Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada. LA - eng GR - MOP-142313/CIHR/Canada PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20181016 PL - United States TA - Oncoimmunology JT - Oncoimmunology JID - 101570526 PMC - PMC6343789 OTO - NOTNLM OT - IL-33 OT - Regulatory T cells OT - ST2 OT - amphiregulin OT - breast cancer OT - metastasis EDAT- 2019/02/05 06:00 MHDA- 2019/02/05 06:01 PMCR- 2019/10/16 CRDT- 2019/02/05 06:00 PHST- 2017/12/19 00:00 [received] PHST- 2018/09/11 00:00 [revised] PHST- 2018/09/13 00:00 [accepted] PHST- 2019/02/05 06:00 [entrez] PHST- 2019/02/05 06:00 [pubmed] PHST- 2019/02/05 06:01 [medline] PHST- 2019/10/16 00:00 [pmc-release] AID - 1527497 [pii] AID - 10.1080/2162402X.2018.1527497 [doi] PST - epublish SO - Oncoimmunology. 2018 Oct 16;8(2):e1527497. doi: 10.1080/2162402X.2018.1527497. eCollection 2019.