ABSTRACT
BACKGROUND: Early-life respiratory infections and asthma are major health burdens during childhood. Markers predicting an increased risk for early-life respiratory diseases are sparse. Here, we identified the predictive value of ultrasound-monitored fetal lung growth for the risk of early-life respiratory infections and asthma. METHODS: Fetal lung size was serially assessed at standardized time points by transabdominal ultrasound in pregnant women participating in a pregnancy cohort. Correlations between fetal lung growth and respiratory infections in infancy or early-onset asthma at five years were examined. Machine-learning models relying on extreme gradient boosting regressor or classifier algorithms were developed to predict respiratory infection or asthma risk based on fetal lung growth. For model development and validation, study participants were randomly divided into a training and a testing group, respectively, by the employed algorithm. RESULTS: Enhanced fetal lung growth throughout pregnancy predicted a lower early-life respiratory infection risk. Male sex was associated with a higher risk for respiratory infections in infancy. Fetal lung growth could also predict the risk of asthma at five years of age. We designed three machine-learning models to predict the risk and number of infections in infancy as well as the risk of early-onset asthma. The models' R2 values were 0.92, 0.90 and 0.93, respectively, underscoring a high accuracy and agreement between the actual and predicted values. Influential variables included known risk factors and novel predictors, such as ultrasound-monitored fetal lung growth. CONCLUSION: Sonographic monitoring of fetal lung growth allows to predict the risk for early-life respiratory infections and asthma.
ABSTRACT
Metastasis is a cancer-related systemic disease and is responsible for the greatest mortality rate among cancer patients. Interestingly, the interaction between the immune system and cancer cells seems to play a key role in metastasis formation in the target organ. However, this complex network is only partially understood. We previously found that IL-22 produced by tissue resident iNKT17 cells promotes cancer cell extravasation, the early step of metastasis. Based on these data, we aimed here to decipher the role of IL-22 in the last step of metastasis formation. We found that IL-22 levels were increased in established metastatic sites in both human and mouse. We also found that Th22 cells were the key source of IL-22 in established metastasis sites, and that deletion of IL-22 in CD4+ T cells was protective in liver metastasis formation. Accordingly, the administration of a murine IL-22 neutralizing antibody in the establishment of metastasis formation significantly reduced the metastatic burden in a mouse model. Mechanistically, IL-22-producing Th22 cells promoted angiogenesis in established metastasis sites. In conclusion, our findings highlight that IL-22 is equally as important in contributing to metastasis formation at late metastatic stages, and thus, identify it as a novel therapeutic target in established metastasis.
Subject(s)
CD4-Positive T-Lymphocytes , Liver Neoplasms , Humans , Animals , Mice , Interleukins , Interleukin-22ABSTRACT
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 IL22ra1flox/flox × AlbCre+ 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.
