Interleukin‐33 activates and recruits natural killer cells to inhibit pulmonary metastatic cancer development

Abstract

Increasing evidence suggests that IL‐33 plays an important role in regulating tumor development. However, conflicting results, obtained from numerous studies, have highlighted the divergent functions of IL‐33. The detailed mechanisms by which IL‐33 modulates tumor development merit further investigation. Here, we report that IL‐33 administration can effectively inhibit the development of pulmonary metastasis of breast cancer in a mouse. In our model, IL‐33 promotes the production of TNF‐α by macrophages, which increases IL‐33 specific receptor (ST2) expression on natural killer (NK) cells and is pivotal in IL‐33‐induced NK cell activation. IL‐33 treatment also facilitates the production of CCL5 in the lung by eosinophils and CD8+ T cells, which mediates the recruitment of NK cells to the tumor microenvironment. The systemic activation and local recruitment of NK cells result in potent tumor rejection in the lung. Our study reports a novel mechanism for the IL‐33‐meditated suppression of metastatic cancer and provides potential therapeutic strategies for targeting metastatic tumor.

Blood eosinophilic relative count is prognostic for breast cancer and associated with the presence of tumor at diagnosis and at time of relapse

“…39 Concerning breast cancer, IL-33 can inhibit lung cancer metastasis in Balb/c mice injected with 4T1-Luc cells, promoting the production of TNF-α by macrophages, that induce the expression of ST2, the IL-33 receptor, on NK cells, leading to their activation. 40 IL-33 promotes also the production of CCL5 by eosinophils and CD8+ T cells that recruit NK cells at tumor site. 40 In other studies, IL-33 administration in breast cancer-bearing mice induces tumor progression through intratumoral accumulation of monocytic myeloid-derived suppressor cells (MDSC) and Foxp3+ Tregs cells, reducing the cytotoxicity and the tumor infiltration by NK cells, inducing cell proliferation and blood vessel density.…”

“…40 IL-33 promotes also the production of CCL5 by eosinophils and CD8+ T cells that recruit NK cells at tumor site. 40 In other studies, IL-33 administration in breast cancer-bearing mice induces tumor progression through intratumoral accumulation of monocytic myeloid-derived suppressor cells (MDSC) and Foxp3+ Tregs cells, reducing the cytotoxicity and the tumor infiltration by NK cells, inducing cell proliferation and blood vessel density. 41,42 Intravenous or intraperitoneal administration of IL-17E (IL-25) in a variety of xenograft tumor models, including breast cancer, showed an antitumoural activity alone or in combination with specific cancer therapeutics, inducing eosinophil expansion through the production of IL-5.…”

Anti-Tumorigenic Activities of IL-33: A Mechanistic Insight

“…Transgenic expression of IL-33 in B16 or 4T1 tumor cells (20) or in the host (21), as well as exogenous administration of the recombinant protein (22) induce the recruitment of activated (IFN-g + CD107 + ) CD8 + T and NK cells in the TME, which inhibited tumor growth in mice. In a breast cancer model, IL-33 induced the recruitment and activation of NK cells to the lung that prevented pulmonary metastasis onset (23). IL-33 can increase the cytotoxicity of CD8 + T cells and NK cells also in vitro, indicating a direct action (21).…”

Exosomal MicroRNAs as Mediators of Cellular Interactions Between Cancer Cells and Macrophages

“…NK cells suppress tumor immune evasion by IFN-γ (14). NK cells suppress the metastatic potential of cancer cells by IL-33 (15). Tryptase released by mast cells enhances tumor cell metastasis through the janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway (16).…”