Wiley, International Journal of Cancer, 7(134), p. 1669-1682, 2013
DOI: 10.1002/ijc.28481
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The role of IL-33/ST2 pathway in antitumour immunity is unclear. Using 4T1 breast cancer model we demonstrate time-dependent increase of endogenous IL-33 at both the mRNA and protein level in primary tumours and metastatic lungs during cancer progression. Administration of IL-33 accelerated tumour growth and development of lung and liver metastases which was associated with increased intratumoural accumulation of CD11b(+) Gr-1(+) TGF-β1(+) MDSCs that expressed IL-13α1R, IL-13 producing Lin(-) Sca-1(+) ST2(+) innate lymphoid cells (ILCs) and CD4(+) Foxp3(+) ST2(+) IL-10(+) Tregs compared to untreated mice. Higher incidence of monocytic vs. granulocytic MDSCs and plasmocytoid vs. conventional dendritic cells (DCs) were present in mammary tumours of IL-33 treated mice. Intratumoural NKp46(+) NKG2D(+) and NKp46(+) FasL(+) cells were markedly reduced following IL-33 treatment, while PBS-treated ST2-deficient mice had increased frequencies of these tumouricidal NK cells compared to untreated wild-type mice. IL-33 promoted intratumoural cell proliferation and neovascularization which was attenuated in the absence of ST2. Tumour bearing mice given IL-33 had increased percentages of splenic MDSCs, Lin(-) Sca-1(+) ILCs, IL-10 expressing CD11c(+) DCs and alternatively activated M2 macrophages and higher circulating levels of IL-10 and IL-13. A significantly reduced NK cell, but not CD8(+) T-cell cytotoxicity in IL-33-treated mice was observed and the mammary tumour progression was not affected when CD8(+) T cells were in vivo depleted. We show a previously unrecognized role for IL-33 in promoting breast cancer progression through increased intratumoural accumulation of immunosuppressive cells and by diminishing innate antitumour immunity. IL-33 may be therefore considered as an important mediator in the regulation of breast cancer progression. © 2013 Wiley Periodicals, Inc.