Interleukin-33/ST2 axis promotes breast cancer growth and metastases by facilitating intratumoral accumulation of immunosuppressive and innate lymphoid cells

Abstract

The role of IL-33/ST2 pathway in antitumor immunity is unclear. Using 4T1 breast cancer model we demonstrate time-dependent increase of endogenous IL-33 at both the mRNA and protein levels in primary tumors and metastatic lungs during cancer progression. Administration of IL-33 accelerated tumor growth and development of lung and liver metastases, which was associated with increased intratumoral accumulation of CD11b+Gr-1+ TGF-β1 + myeloid-derived suppressor cells (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) was present in mammary tumors of IL-33-treated mice. Intratumoral NKp46+NKG2D+ and NKp46+FasL+ cells were markedly reduced after IL-33 treatment, while phosphate-buffered saline-treated ST2-deficient mice had increased frequencies of these tumoricidal natural killer (NK) cells compared to untreated wild-type mice. IL-33 promoted intratumoral cell proliferation and neovascularization, which was attenuated in the absence of ST2. Tumor-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 tumor 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 intratumoral accumulation of immunosuppressive cells and by diminishing innate antitumor immunity. Therefore, IL-33 may be considered as an important mediator in the regulation of breast cancer progression. What's new? This study employed a breast cancer cell line to investigate the role of interleukin-33 in cancer progression. They found more IL-33 in the cells as the disease advanced, and they showed that administring IL-33 to mice accelerated growth and metastasis. The increased levels of IL-33 sped cancer progression both by hindering antitumor immunity and by encouraging angiogenesis. Understanding the effects of IL-33 on cancer suggests possible avenues for tumor immunotherapy. © 2013 UICC.