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Interleukin-33 in tumorigenesis, tumor immune evasion, and cancer immunotherapy

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Abstract

Interleukin-33 (IL-33) is a member of the IL-1 gene family and mainly expressed in the nucleus of tissue lining cells, stromal cells, and activated myeloid cells. IL-33 is considered a damage-associated molecular pattern (DAMP) molecule and plays an important role in many physiological and pathological settings such as tissue repair, allergy, autoimmune disease, infectious disease, and cancer. The biological functions of IL-33 include maintaining tissue homeostasis, enhancing type 1 and 2 cellular immune responses, and mediating fibrosis during chronic inflammation. IL-33 exerts diverse functions through signaling via its receptor ST2, which is expressed in many types of cells including regulatory T cells (Treg), group 2 innate lymphoid cells (ILC2s), myeloid cells, cytotoxic NK cells, Th2 cells, Th1 cells, and CD8+ T cells. Tumor development results in downregulation of IL-33 in epithelial cells but upregulation of IL-33 in the tumor stroma and serum. The current data suggest that IL-33 expression in tumor cells increases immunogenicity and promotes type 1 antitumor immune responses through CD8+ T cells and NK cells, whereas IL-33 in tumor stroma and serum facilitates immune suppression via Treg and myeloid-derived suppressor cell (MDSC). Understanding the role of IL-33 in cancer immunobiology sheds lights on targeting this cytokine for cancer immunotherapy.

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Acknowledgments

The project was mainly supported by the National Institutes of Health through Grant Numbers R21CA167229 (BL), Roswell Park Cancer Institute/University of Pittsburgh Cancer Institute Ovarian Cancer Specialized Programs of Research Excellence Grants P50CA159981 (to BL), and National Natural Science Foundation of China Grants 31428005 (to BL and JJ). QW is supported by grants from National Natural Science Foundation of China (81373115) and National Program on Key Basic Research Project (2014CB542101).

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Lu, B., Yang, M. & Wang, Q. Interleukin-33 in tumorigenesis, tumor immune evasion, and cancer immunotherapy. J Mol Med 94, 535–543 (2016). https://doi.org/10.1007/s00109-016-1397-0

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