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.

Obesity-induced diabetes is associated with low-grade inflammation in adipose tissue and macrophage infiltration of islets. We show that ablation of galectin-3 (Gal-3), a galactoside-binding lectin, accelerates high-fat diet–induced obesity and diabetes. Obese LGALS3−/− mice have increased body weight, amount of total visceral adipose tissue (VAT), fasting blood glucose and insulin levels, homeostasis model assessment of insulin resistance, and markers of systemic inflammation compared with diet-matched wild-type (WT) animals. VAT of obese LGALS3−/− mice exhibited increased incidence of type 1 T and NKT lymphocytes and proinflammatory CD11c+CD11b+ macrophages and decreased CD4+CD25+FoxP3+ regulatory T cells and M2 macrophages. Pronounced mononuclear cell infiltrate, increased expression of NLRP3 inflammasome and interleukin-1β (IL-1β) in macrophages, and increased accumulation of advanced glycation end products (AGEs) and receptor for AGE (RAGE) expression were present in pancreatic islets of obese LGALS3−/− animals accompanied with elevated phosphorylated nuclear factor-κB (NF-κB) p65 and mature caspase-1 protein expression in pancreatic tissue and VAT. In vitro stimulation of LGALS3−/− peritoneal macrophages with lipopolysaccharide (LPS) and saturated fatty acid palmitate caused increased caspase-1–dependent IL-1β production and increased phosphorylation of NF-κB p65 compared with WT cells. Transfection of LGALS3−/− macrophages with NLRP3 small interfering RNA attenuated IL-1β production in response to palmitate and LPS plus palmitate. Obtained results suggest important protective roles for Gal-3 in obesity-induced inflammation and diabetes.

ST2 is a member of the IL‐1 receptor family and IL‐33 was recently identified as its natural ligand. The IL‐33/ST2 pathway regulates Th1/Th2 immune responses in autoimmune and inflammatory conditions, but the role of ST2 signaling in tumor growth and metastasis has not been investigated. We aimed to investigate whether ST2 gene deletion affects tumor appearance, growth, and metastasis, and antitumor immunity in an experimental metastatic breast cancer model. Deletion of ST2 in BALB/c mice bearing mammary carcinoma attenuated tumor growth and metastasis, which was accompanied by increased serum levels of IL‐17, IFN‐γ, and TNF‐α and decreased IL‐4. Tumor‐bearing ST2^−/− mice had significantly higher percentages of activated CD27^highCD11b^high NK cells, CD69⁺ and KLRG⁻ NK cells and higher cytotoxic activity of splenocytes, NK cells, and CD8⁺ T cells in vitro. A significantly higher number of NK cells expressing IFN‐γ were found in ST2^−/− mice compared with WT recipients. In vivo depletion of CD8⁺ or NK cells revealed a key role for NK cells in enhanced antitumor immunity in ST2^−/− mice. We report for the first time that suppressed breast cancer progression and metastasis in mice lacking ST2 corresponds mainly with enhanced cytotoxic activity of NK cells, and increased systemic Th1/Th17 cytokines.