A Critical Role of the IL-22-IL-22 Binding Protein Axis in Hepatocellular Carcinoma

Simple Summary Hepatocellular carcinoma (HCC) still poses a major challenge for curative treatment. Although some new therapeutic options arose during the last decade, the overall prognosis remains poor. New therapies might include the modification of tumor-promoting or -inhibiting mediators of the immune system, such as interleukin (IL)-22 and its natural antagonist IL-22 binding protein (IL-22BP). Thus, this study aimed to investigate the role and underlying mechanisms of IL-22 and IL-22BP signaling in liver cancer. Using two different mouse models, we found that IL-22 promoted HCC development, while IL-22BP led to reduced tumor growth. IL-22 was mainly produced by a subset of T cells in HCC, whereas IL-22BP was abundantly secreted by neutrophils. Importantly, we identified hepatocytes as a major target of this pathological IL-22-signaling. Moreover, abrogation of IL-22 signaling in hepatocytes reduced STEAP4 expression-a known oncogene-in an HCC mouse model in vivo, and STEAP4 expression correlated with IL22 levels in human HCC samples. Taken together, these data might pave the way for new therapeutical approaches by blocking IL-22 or its downstream signaling in HCC. Hepatocellular carcinoma (HCC) ranks among the five most common cancer entities worldwide and leads to hundred-thousands of deaths every year. Despite some groundbreaking therapeutical revelations during the last years, the overall prognosis remains poor. Although the immune system fights malignant transformations with a robust anti-tumor response, certain immune mediators have also been shown to promote cancer development. For example, interleukin (IL)-22 has been associated with HCC progression and worsened prognosis in multiple studies. However, the underlying mechanisms of the pathological role of IL-22-signaling as well as the role of its natural antagonist IL-22 binding protein (IL-22BP) in HCC remain elusive. Here, we corroborate the pathogenic role of IL-22 in HCC by taking advantage of two mouse models. Moreover, we observed a protective role of IL-22BP during liver carcinogenesis. While IL-22 was mainly produced by CD4(+) T cells in HCC, IL-22BP was abundantly expressed by neutrophils during liver carcinogenesis. Hepatocytes could be identified as a major target of this pathological IL-22-signaling. Moreover, abrogation of IL-22 signaling in hepatocytes in IL22ra1(flox/flox) x Alb(Cre+) mice reduced STEAP4 expression-a known oncogene-in HCC in vivo. Likewise, STEAP4 expression correlated with IL22 levels in human HCC samples, but not in healthy liver specimens. In conclusion, these data encourage the development of therapeutical approaches that target the IL-22-IL-22BP axis in HCC.