IL-10 dampens antitumor immunity and promotes liver metastasis via PD-L1 induction.

BACKGROUND & AIMS: The liver is one of the organs most commonly affected by metastasis. The presence of liver metastases has been reported to be responsible for an immunosuppressive microenvironment and diminished immunotherapy efficacy. Herein, we aimed to investigate the role of IL-10 in liver metastasis and to determine how its modulation could affect the efficacy of immunotherapy in vivo. METHODS: To induce spontaneous or forced liver metastasis in mice, murine cancer cells (MC38) or colon tumor organoids were injected into the cecum or the spleen, respectively. Mice with complete and cell type-specific deletion of IL-10 and IL-10 receptor alpha were used to identify the source and the target of IL-10 during metastasis formation. Programmed death ligand 1 (PD-L1)-deficient mice were used to test the role of this checkpoint. Flow cytometry was applied to characterize the regulation of PD-L1 by IL-10. RESULTS: We found that Il10-deficient mice and mice treated with IL-10 receptor alpha antibodies were protected against liver metastasis formation. Furthermore, by using IL-10 reporter mice, we demonstrated that Foxp3+ regulatory T cells (Tregs) were the major cellular source of IL-10 in liver metastatic sites. Accordingly, deletion of IL-10 in Tregs, but not in myeloid cells, led to reduced liver metastasis. Mechanistically, IL-10 acted on Tregs in an autocrine manner, thereby further amplifying IL-10 production. Furthermore, IL-10 acted on myeloid cells, i.e. monocytes, and induced the upregulation of the immune checkpoint protein PD-L1. Finally, the PD-L1/PD-1 axis attenuated CD8-dependent cytotoxicity against metastatic lesions. CONCLUSIONS: Treg-derived IL-10 upregulates PD-L1 expression in monocytes, which in turn reduces CD8+ T-cell infiltration and related antitumor immunity in the context of colorectal cancer-derived liver metastases. These findings provide the basis for future monitoring and targeting of IL-10 in colorectal cancer-derived liver metastases. IMPACT AND IMPLICATIONS: Liver metastasis diminishes the effectiveness of immunotherapy and increases the mortality rate in patients with colorectal cancer. We investigated the role of IL-10 in liver metastasis formation and assessed its impact on the effectiveness of immunotherapy. Our data show that IL-10 is a pro-metastatic factor involved in liver metastasis formation and that it acts as a regulator of PD-L1. This provides the basis for future monitoring and targeting of IL-10 in colorectal cancer-derived liver metastasis.

Management of Esophageal Cancer-Associated Respiratory-Digestive Tract Fistulas.

Respiratory-digestive tract fistulas are fatal complications that occur in esophageal cancer treatment. Interdisciplinary treatment strategies are still evolving, especially in anatomical treatment stratification. Thus, this study aims to evaluate general therapeutic strategies for this rare condition. Medical records were reviewed for esophageal cancer-associated respiratory-digestive tract fistula patients treated between January 2008 and September 2021. Fistulas were classified according to being surgery- and tumor-associated. Treatment strategies, clinical success, and survival were analyzed. A total of 51 patients were identified: 28 had tumor-associated fistulas and 23 surgery-associated fistulas. Risk factors for fistula development such as radiation (OR = 0.290, p = 0.64) or stent implantation (OR = 1.917, p = 0.84) did not correlate with lack of symptom control for RDF patients. In contrast, advanced lymph node metastasis as another risk factor was associated with persistent symptoms after treatment for RDF patients (OR = 0.611, p = 0.01). Clinical success significantly correlated with bilateral fistula repair in surgery-associated fistulas (p = 0.01), while tumor-associated fistulas benefited the most from non-surgical (p = 0.04) or combined surgical and non-surgical intervention (p = 0.04) and a bilateral fistula repair (p = 0.02) in terms of overall survival. The therapeutic strategy should aim for bilateral fistula closure. A multidisciplinary, stepwise approach might have the best chance for restoration or symptom control with optimized overall survival in selected patients.

Risk stratification of cirrhotic patients undergoing esophagectomy for esophageal cancer: A single-centre experience.

BACKGROUND: Concomitant liver cirrhosis is a crucial risk factor for major surgeries. However, only few data are available concerning cirrhotic patients requiring esophagectomy for malignant disease. METHODS: From a prospectively maintained database of esophageal cancer patients, who underwent curative esophagectomy between 01/2012 and 01/2016, patients with concomitant liver cirrhosis (liver-cirrhotic patients, LCP) were compared to non-liver-cirrhotic patients (NLCP). RESULTS: Of 170 patients, 14 cirrhotic patients with predominately low MELD scores (≤ 9, 64.3%) were identified. Perioperative outcome was significantly worse for LCP, as proofed by 30-day (57.1% vs. 7.7, p<0.001) and 90-day mortality (64.3% vs. 9.6%, p<0.001), anastomotic leakage rate (64.3 vs. 22.3%, p = 0.002) and sepsis (57.1 vs. 21.5%, p = 0.006). Even after adjustment for age, gender, comorbidities, and surgical approach, LCP revealed higher odds for 30-day and 90-day mortality compared to NLCP. Moreover, 5-year survival analysis showed a significantly poorer long-term outcome of LCP (p = 0.023). For risk stratification, none of the common cirrhosis scores proved prognostic impact, whereas components as Bilirubin (auROC 94.4%), INR (auROC = 90.0%), and preoperative ascites (p = 0.038) correlated significantly with the perioperative outcome. CONCLUSION: Curative esophagectomy for cirrhotic patients is associated with a dismal prognosis and should be evaluated critically. While MELD and Child score failed to predict perioperative mortality, Bilirubin and INR proofed excellent prognostic capacity in this cohort.

CD147 expression lacks prognostic relevance in esophageal cancer.

INTRODUCTION: The role of CD147 as an important indicator of tumor prognosis remains controversially discussed in literature. We focused on the prognostic significance of CD147 expression in esophageal cancer patients. While some studies report that CD147 is an unfavorable prognostic factor in esophageal squamous cell carcinoma, others showed no significant correlation. However, only one study draws attention to the significance of CD147 in esophageal adenocarcinoma, which is one of the most rapidly increasing neoplasms in the western world. METHODS: To finally clarify the impact of CD147 as a prognostic factor, especially for esophageal adenocarcinomas, we analyzed CD147 expression in a tissue microarray of 359 esophageal adenocarcinomas and 254 esophageal squamous cell cancer specimens. For the immuno-histochemical analysis, we used a primary antibody specific for CD147. Staining intensity and proportion of positive tumor cells were scored (negative, weak, moderate, strong staining). These findings were compared to normal esophageal tissue and correlated to the histopathological tumor phenotype and survival data. RESULTS: CD147 expression was detectable in weak intensities in benign esophageal tissue (85.78%) and expressed in predominately moderate to strong intensities in esophageal cancer (88.34%). Strong CD147 immunostaining was linked to increased infiltration depth (p = 0.015) and differentiation (p = 0.016) in esophageal squamous cell cancer but revealed no significant correlation with histopathology of adenocarcinoma. Moreover, CD147 intensity was unrelated to overall survival in this collective for both subtypes of esophageal cancer. CONCLUSION: Thus, our data show that CD147 has no prognostic value, neither in esophageal adenocarcinoma nor squamous cell carcinoma.

Trends in trabecular architecture and bone mineral density distribution in 152 individuals aged 30-90 years.

The strength of trabecular bone depends on its microarchitecture and its tissue level properties. However, the interrelation between these two determinants of bone quality and their relation to age remain to be clarified. Iliac crest bone cores (n=152) from individuals aged 30-90 years were analyzed by quantitative backscattered electron imaging. Univariate and multivariate analyses were conducted to determine whether epidemiological parameters (age, sex or BMI), structural histomorphometrical variables (BV/TV, Tb.Th, Tb.N and Tb.Sp) and osteoid-related indices (OV/BV, OS/BS or O.Th) predict the degree of bone mineralization. While sex and BMI were not associated with bone mineralization, age was positively correlated with the most frequently occurring calcium concentrations (Ca peak), the percentage of highly mineralized bone areas (Ca high) and, in the case of adjusted covariates, also the mean calcium content (Ca mean). Bone volume fraction and trabecular thickness were both negatively correlated with Ca mean. However, trabecular thickness was additionally associated with Ca peak, Ca high as well as the amount of low mineralized bone (Ca low) and was the only structural parameter predicting bone mineralization independent of age. Furthermore, our analyses demonstrated that osteoid variables - within a normal range (<2% OV/BV) - were significantly associated with all mineralization parameters and represent the only predictor for the mineralization heterogeneity (Ca width). Taken together, we showed that elevated trabecular bone mineralization correlates with aging and bone loss. However, these associations are attributable to trabecular thinning that comes along with high bone mineralization due to the loss of low mineralized bone surfaces. Therefore, we demonstrated that the degree of areally resolved bone mineral is primarily associated with the amount of physiological osteoid present and the thickness of mineralized bone in trabeculae.