IL-33 Released in the Liver Inhibits Tumor Growth via Promotion of T Cells

IL-33 Released in the Liver Inhibits Tumor Growth via Promotion of T Cells

*Based on: Ziqi Jin, Lei Lei, Dandan Lin, Yonghao Liu, Yuan Song, Huanle Gong, Ying Zhu, Yu Mei, Bo Hu, YanWu, Guangbo Zhang, Haiyan Liu. (Nov. 16^th, 2018). IL-33 Released in the Liver Inhibits Tumor Growth via Promotion of CD4⁺ and CD8⁺ T Cell Responses in Hepatocellular Carcinoma. The Journal of Immunology.

IL-33, a member of the IL-1 family, is a an interleukin. Interleukins are a type of protein known as a cytokine. Cytokines are any number of substances that are used for cell signaling and communication, though interleukins are a specific type of cytokine that are made by one leukocyte, white blood cell, and act on another leukocyte (1). Cytokines possess both protumor and antitumor roles and both protumor and antitumor functions of IL-33 have been shown in previous studies. IL-33 is abundantly expressed in normal tissues and can localize to the nucleus, where genetic material is located. When released by epithelial cells (the thin tissue forming our outer layer of the body and also the lining of our gut) and immune system cells, IL-33 functions as an alarm to the body that there is a threat that needs to be addressed. It can induce two types of immune responses known as type 1 and type 2 immune responses. The primary response is inflammation.

The specific role of IL-33 release in tumor development is still unclear. However, serum IL-33 levels are increased in many cancers such as gastric cancer, murine hepatocellular carcinoma (HCC), head and neck cancer, breast cancer, and lung cancer (4-8). In this study they examined the function of released IL-33 in HCC. HCC is the most common cancer of the liver, representing 85% of liver malignancies and ranks as the third most common cause of cancer-related death worldwide (2).

This study found that tumor growth was greatly inhibited by IL-33 release, but this antitumor effect was dependent on suppression of tumorgenicity 2 (ST2). ST2 is a member of the IL-1 family of receptors (3) and the interaction between IL-33 and ST2 to known to lead to cell proliferation, survival, and production of inflammatory mediators. The study found that the antitumor effect of IL-33 was diminished in ST2^-/- mice, meaning mice lacking ST2. This demonstrates that IL-33 release inhibits HCC tumor development in an ST2-dependent manner.

Additionally, the study found that HCC patients with high IL-33 expression had prolonged survival compared with the patients with low IL-33 expression. It was found that there were increased numbers of activated and effector CD4⁺ and CD8⁺ T cells in both the spleen and liver of IL-33-expressing tumor-bearing mice. CD4⁺ T cells are helper white blood cells and CD8⁺ T cells are killer white blood cells. Both these cells are produced in the thymus and actively participate in immune responses. An upregulation of IFN-y production in IL-33-expressing tumor-bearing mice was also seen. IFN-y is a cytokine that is critical for innate and adaptive immunity against viral infections.

The lab’s in vitro experiments, performed in a test tube, further showed that IL-33 could directly activate CD4⁺ and CD8⁺ T cells. Depletion of CD4⁺ and CD8⁺ T cells in vivo, performed in a living organism, diminished the anti-tumor activity of IL-33, suggesting that the anti-tumor function of IL-33 is mediated by both CD4⁺ and CD8⁺ T cells.

Why is this important?

            This study demonstrated that IL-33 release promoted antitumor T cell responses and showed specifically, that IL-33 could inhibit HCC development via promoting antitumor CD4⁺ and CD8⁺ T cell responses in an ST2-dependent manner. In ever HCC model they examined, IL-33 inhibited HCC tumor development. The inflammatory cytokines functioning as alarms are critical in establishing the organ microenvironment. Understanding the regulatory functions of cytokines during tumor development can shed light on the immune interactions in the tumor microenvironment and can provide therapeutic strategies for HCC and early intervention.

New Questions/Next Steps

            The study found that Treg expression also increased in the spleen and liver of IL-33-expressing tumor-bearing mice. These cells could compromise and be targeted to enhance IL-33 mediated antitumor immune response. Treg depletion and IL-33 may work synergistically for tumor therapy, which could be further investigated in HCC models.

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