IL-22 has dual functions during tumorigenesis. Short term IL-22 production protects against genotoxic stress, whereas uncontrolled IL-22 activity promotes tumor growth; therefore, tight regulation of IL-22 is essential. TGF-β1 promotes the differentiation of Th17 cells, which are known to be a major source of IL-22, but the effect of TGF-β signaling on the production of IL-22 in CD4+ T cells is controversial. Here we show an increased presence of IL-17+IL-22+ cells and TGF-β1 in colorectal cancer compared to normal adjacent tissue, whereas the frequency of IL-22 single producing cells is not changed. Accordingly, TGF-β signaling in CD4 + T cells (specifically Th17 cells) promotes the emergence of IL-22-producing Th17 cells and thereby tumorigenesis in mice. IL-22 single producing T cells, however, are not dependent on TGF-β signaling. We show that TGF-β, via AhR induction, and PI3K signaling promotes IL-22 production in Th17 cells.

Pancreatic ductal adenocarcinoma (PDAC) is expected to be the second most deadly cancer by 2040, owing to the high incidence of metastatic disease and limited responses to treatment1,2. Less than half of all patients respond to the primary treatment for PDAC, chemotherapy3,4, and genetic alterations alone cannot explain this5. Diet is an environmental factor that can influence the response to therapies, but its role in PDAC is unclear. Here, using shotgun metagenomic sequencing and metabolomic screening, we show that the microbiota-derived tryptophan metabolite indole-3-acetic acid (3-IAA) is enriched in patients who respond to treatment. Faecal microbiota transplantation, short-term dietary manipulation of tryptophan and oral 3-IAA administration increase the efficacy of chemotherapy in humanized gnotobiotic mouse models of PDAC. Using a combination of loss- and gain-of-function experiments, we show that the efficacy of 3-IAA and chemotherapy is licensed by neutrophil-derived myeloperoxidase. Myeloperoxidase oxidizes 3-IAA, which in combination with chemotherapy induces a downregulation of the reactive oxygen species (ROS)-degrading enzymes glutathione peroxidase 3 and glutathione peroxidase 7. All of this results in the accumulation of ROS and the downregulation of autophagy in cancer cells, which compromises their metabolic fitness and, ultimately, their proliferation. In humans, we observed a significant correlation between the levels of 3-IAA and the efficacy of therapy in two independent PDAC cohorts. In summary, we identify a microbiota-derived metabolite that has clinical implications in the treatment of PDAC, and provide a motivation for considering nutritional interventions during the treatment of patients with cancer.

Objective: Aim of this prospective study was to evaluate the prognostic significance of disseminated tumor cells (DTCs) and circulating tumor cells (CTCs) in 1 cohort of patients with esophageal cancer (EC). Background: Hematogenous tumor cell dissemination is a key event in tumor progression, and clinical significance of DTCs and CTCs are controversially discussed in the literature. However, evaluation of both biomarker in 1 patient's cohort has not been described before. Methods: In this prospective, single-center study, 76 patients with preoperatively nonmetastatic staged EC were included. The CellSearch system was used to enumerate CTCs. Bone marrow was aspirated from the iliac crest and cells were enriched by Ficoll density gradient centrifugation. DTCs were immunostained with the pan-keratin antibody A45-B/B3. Results: Fifteen of 76 patients (19.7%) harbored CTCs, whereas in 13 of 76 patients (17.1%), DTCs could be detected. In only 3 patients (3.9%), CTCs and DTCs were detected simultaneously, whereas concordant results (DTC/CTC negative and DTC/CTC positive) were found in 54 patients (71.1%). Surprisingly, only patients with CTCs showed significant shorter overall and relapse-free survival (P = 0.038 and P = 0.004, respectively). Multivariate analyses revealed that only the CTC status was an independent predictor of overall and relapse-free survival (P = 0.007 and P < 0.001, respectively). Conclusions: This is the first study analyzing CTC and DTC status in 1 cohort of nonmetastatic patients with EC. In this early disease stage, only the CTC status was an independent, prognostic marker suitable and easy to use for clinical staging of patients with EC.

No abstract

No abstract

Background/Aim: The clinical significance of circulating tumor cells (CTC) in non-metastatic esophageal cancer (EC) remains controversial and the cellular and molecular characteristics of CTCs are poorly understood. Especially the frequency and oncological impact of HER2 expression in CTCs in patients with EC have not been evaluated until now. Materials and Methods: In this singlecenter, prospective study, peripheral blood samples were obtained preoperatively from 45 patients who were diagnosed with resectable EC. CTC detection and HER2 expression were performed using the CellSearch System. Data were correlated with clinicopathological parameters and patient outcomes. Results: The study included 13 patients with squamous cell carcinomas (SCC) and 32 patients with adenocarcinomas (AC). HER2 gene amplification in the primary tumor was detected in 9.1% of patients. One or more CTCs were detected in 15.6% (SCC 1/13; AC 6/32) of the patients. None of the detected CTCs showed HER2 expression. Patients with CTCs showed significantly shorter relapse-free (p<0.001) and overall survival (p=0.015) than CTC-negative patients. Conclusion. This is the first study analyzing HER2 expression and the clinical significance of CTCs in patients with non-metastatic EC using an automated immunomagnetic detection system. HER2 expression in CTCs is very rare in patients with nonmetastatic EC and seems to have a low clinical and oncological impact.Cancer of the esophagus, despite technical advances, is still a highly lethal malignancy. Most esophageal cancers (EC) are squamous cell or adenocarcinomas. Although the incidence of squamous cell carcinoma (SCC) is decreasing, the incidence of adenocarcinoma (AC) arising from Barrett's esophagus is dramatically increasing.More than two thirds of all patients with esophageal cancer develop metastases or local recurrence and circulating tumor cells (CTCs) or disseminated tumor cells are supposedly playing a key part in this development (1-3). Previous studies showed that the presence of CTCs is correlated with shorter overall survival in patients with metastatic disease (1,4,5). In EC, CTC detection is an independent prognostic marker of overall and recurrence-free survival. However, its significance in non-metastatic EC remains controversial and the molecular biological characteristics of CTCs are poorly understood (4, 6).The human epidermal growth factor receptor gene HER2 is known to play a role in the development of malignancies and is often linked to a poor prognosis, for example in breast cancer (7). The HER2-inhibitor trastuzumab has been shown to be very effective against breast cancer overexpression HER2 (8, 9). In EC however, there is no correlation between the presence of HER2 in the primary tumor and patient survival (10-12). Stoecklein et al. showed that HER2 gain in at least a single disseminated tumor cell (DTC) in bone marrow was a prognostic factor of poor survival (13). However, the frequency and oncological impact of HER2 expression in CTCs in patients with EC has not been eval...

No abstract

Objective Reflux promotes esophageal adenocarcinomas (EACs) creating a chronic inflammatory environment. Survival rates are low due to early local recurrences and distant metastasis. Hence, there is a need for new potential treatment options like immunotherapies. However, the inflammatory microenvironment in EACs and its impact on patient outcome remain to be fully understood. Methods mRNA expression levels of pro-and anti-inflammatory markers in 39 EAC patients without neoadjuvant radiochemotherapy were measured. Data were confirmed using flow cytometric analysis of freshly resected surgical specimens. Inflammatory alterations in premalignant lesions of Barrett's esophagus were analyzed by immunohistochemistry. Results Expression levels of IL22 were reduced in EAC, while expression levels of FOXP3, IL10 and CTLA4 were increased. Flow cytometry demonstrated a strong infiltration of CD4 + T cells with a reduction in CD4 + T cells producing IL-22 or IL-17A. We also observed an increase in CD4 + CD127 low FOXP3 + cells producing IL-10. Accumulation of FOXP3 + T cells occurred prior to malignant changes. High expression of IL10 and low expression of IL22 in EAC were associated with reduced overall survival. Moreover, increased expression of IL10, CTLA4 and PD1 in the unaltered esophageal mucosa distant to the EAC was also linked with an unfavorable prognosis. Conclusion EAC shows an anti-inflammatory environment, which strongly affects patient survival. The microscopically unaltered peritumoral tissue shows a similar anti-inflammatory pattern indicating an immunological field effect, which might contribute to early local recurrences despite radical resection. These data suggest that using checkpoint inhibitors targeting anti-inflammatory T cells would be a promising therapeutic strategy in EAC.