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 tenfold 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.

Regulation of regulatory T cells in cancer

“…Although the authors excluded both immune and tumour cells, the precise identity of the cells targeted by the Treg‐derived Amphiregulin remains to be addressed. In line with these data, an increased proportion of Treg cells were shown to be ST2 + in both primary orthotopic mouse mammary carcinoma and lung metastases, and ST2 + lung tumour Treg cells, but not ST2 − , were shown to produce Amphiregulin …”

“…Whether the IL-33/ST2 axis on Treg cells plays a role in tumour progression has yet to be established. Interestingly, administration of IL-33 to tumour-bearing mice was shown to expand tumour-infiltrating Treg cells, 98,158 in line with the aforementioned IL-33-driven expansion of Treg cells in healthy tissues. Recent generation of Foxp3-Cre 9 Il1rl1 fl/fl mice 159 should shed light on the relevance of this pathway in vivo.…”

“…In line with these data, an increased proportion of Treg cells were shown to be ST2 + in both primary orthotopic mouse mammary carcinoma and lung metastases, and ST2 + lung tumour Treg cells, but not ST2 À , were shown to produce Amphiregulin. 98 In human breast tumour and healthy adjacent tissue, RNA-sequencing analyses from the Plitas et al 70 study described above revealed that the gene expression profile of tumour-infiltrating Treg cells was similar to those of the tissue-resident Treg cells of the normal breast parenchyma, but distinct from the profile of the CD45RO + activated Treg cells isolated from peripheral blood, used here as a reference of activated Treg cells. Surprisingly though, extraction of the TCR repertoire of these cells from RNA-sequencing data did not support the hypothesis of local tissue-resident Treg cell expansion: only low clonal overlap was found between the tumour-infiltrating Treg cells and those from the normal adjacent tissue.…”

Targeting myeloid-derived suppressor cells in combination with primary mammary tumor resection reduces metastatic growth in the lungs

“…5b-d). Eosinophils remained elevated in the lungs after primary tumor resection, which may be related to the high levels of IL-33 release we have previously observed in the lungs of 4T1 tumor-bearing mice [52] since IL-33 is known to activate eosinophils and induce eosinophilic airway inflammation [53]. Despite the increased eosinophil content in the lungs after tumor resection, we did not find that eosinophils affected 4T1 metastatic tumor growth in the lungs (Additional file 12: Figure S11).…”

Interleukin-1 and Related Cytokines in the Regulation of Inflammation and Immunity

“…Evidence linking IL-33 to tumor promotion include pre-clinical models and human prognostic and genetic associations (Amô r et al, 2018;Ding et al, 2018;Wen et al, 2019). Interestingly IL-33 was associated with stromalcell-driven Treg differentiation in oral squamous cell carcinoma (Wen et al, 2019) and promoted Treg-dependent metastatic mammary tumor growth in the lung (Halvorsen et al, 2018).…”