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

Int J Cancer. 2014 Apr 1;134(7):1669-82. doi: 10.1002/ijc.28481. Epub 2013 Oct 10.


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.

Keywords: 4T1 mammary carcinoma; IL-33; NK cells; T regs; dendritic cells; innate lymphoid cells; myeloid-derived suppressor cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Breast Neoplasms / genetics
  • Breast Neoplasms / immunology*
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / metabolism
  • Cell Growth Processes / genetics
  • Cell Growth Processes / immunology
  • Cell Line, Tumor
  • Disease Progression
  • Female
  • Immunity, Innate / genetics
  • Immunity, Innate / immunology
  • Interleukin-1 Receptor-Like 1 Protein
  • Interleukin-33
  • Interleukins / genetics
  • Interleukins / immunology*
  • Interleukins / metabolism
  • Killer Cells, Natural / immunology
  • Killer Cells, Natural / metabolism
  • Killer Cells, Natural / pathology
  • Lymphocytes / immunology*
  • Lymphocytes / metabolism
  • Lymphocytes / pathology
  • Mammary Neoplasms, Experimental / genetics
  • Mammary Neoplasms, Experimental / immunology
  • Mammary Neoplasms, Experimental / metabolism
  • Mammary Neoplasms, Experimental / pathology
  • Mice
  • Mice, Inbred BALB C
  • Neoplasm Metastasis
  • Receptors, Interleukin / genetics
  • Receptors, Interleukin / immunology*
  • Receptors, Interleukin / metabolism
  • Spleen / immunology
  • Spleen / metabolism
  • Spleen / pathology
  • T-Lymphocytes, Cytotoxic / immunology
  • T-Lymphocytes, Cytotoxic / metabolism
  • T-Lymphocytes, Cytotoxic / pathology


  • Il1rl1 protein, mouse
  • Il33 protein, mouse
  • Interleukin-1 Receptor-Like 1 Protein
  • Interleukin-33
  • Interleukins
  • Receptors, Interleukin