Abstract A50: Interleukin-33 increases ST2+ regulatory T cells and promotes metastatic tumor growth in the lungs in an amphiregulin-dependent manner
Authors: Halvorsen Elizabeth C. , Franks S. Elizabeth , Wadsworth Brennan J. , Harbourne Bryant T. , Cederberg Rachel A. , Steer Catherine A. , Martinez-Gonzalez Itziar , Calder Jack , Lockwood William W. , Bennewith Kevin L. 
Published: June 2021

Abstract
Regulatory T cells (Tregs) can facilitate primary and metastatic tumor growth through the suppression of antitumor immunity. Emerging evidence suggests a distinct role for Tregs in tissue repair and tissue barrier integrity by IL-33 mediated activation of the IL-33 receptor (ST2), causing the production of the epidermal growth factor receptor (EGFR) ligand amphiregulin (AREG). Treg-derived AREG is critical for the repair of infection-induced damage in the lungs, and AREG may induce tumor cell proliferation, invasion, migration or resistance to apoptosis by signaling through EGFR. We have previously shown that immune-suppressive myeloid-derived suppressor cells (MDSCs), macrophages, and Tregs are recruited to the lungs of mice bearing metastatic mammary tumors and promote metastatic growth in the lungs. We now show that IL-33 is dramatically increased in and around metastatic tumor foci in the lungs of mice bearing metastatic murine mammary tumors. We have also found that the majority of Tregs in the lungs of metastatic tumor-bearing mice express ST2, that Tregs express significantly more ST2 than conventional T cells, 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 (pEGFR) in the metastatic lungs. While recombinant AREG did not impact the proliferation of mammary tumor cells in vitro despite inducing a dose-dependent increase in pEGFR, intranasal administration of recombinant AREG resulted in a ten-fold increase in pulmonary metastatic tumor burden in vivo. Further, the intranasal administration of recombinant IL-33 significantly increased metastatic tumor burden in the lungs in an AREG-dependent manner. These data identify ST2+ Tregs as a microenvironmental source of AREG in the lungs of metastatic mammary tumor-bearing mice and show that inhibition of AREG can reduce IL33-mediated increases in metastatic tumor growth. Our findings highlight an important role for IL33 and AREG in promoting metastatic growth and support the development of therapeutic strategies to inhibit AREG to reduce tumor metastases in the lungs.
Citation Format: Elizabeth C. Halvorsen, S. Elizabeth Franks, Brennan J. Wadsworth, Bryant T. Harbourne, Rachel A. Cederberg, Catherine A. Steer, Itziar Martinez-Gonzalez, Jack Calder, William W. Lockwood, Kevin L. Bennewith. Interleukin-33 increases ST2+ regulatory T cells and promotes metastatic tumor growth in the lungs in an amphiregulin-dependent manner [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr A50.