Suppressive effect of interleukin 10 on priming of naive hepatitis C virus-specific CD8+ T cells.

Growing evidence suggests a role for the immunomodulatory cytokine interleukin-10 (IL-10) in hepatitis C virus (HCV)-specific CD8(+) T-cell failure. To address the possible role of IL-10 during priming, we performed in vitro priming experiments with naive HCV-specific CD8(+) T cells and autologous monocyte-derived dendritic cells in the absence or presence of IL-10. Our results showed that IL-10, when present during priming, significantly reduced the frequency of HCV-specific CD8(+) T cells after coculture; It was directly targeting CD8(+) T cells and led to impaired effector cell differentiation. These results may provide a possible mechanistic basis for the association between early IL-10 elevation, T-cell failure, and viral persistence.

Two decades of gastric and gastroesophageal junction cancer surgery.

PURPOSE: Diagnosis and treatment of gastric and gastroesophageal junction cancer have undergone many critical changes during the last two decades. We addressed the question of how clinical reality outside of clinical trials has changed for gastric and gastroesophageal junction cancer patients in a European center for upper gastrointestinal surgery. METHODS: In this retrospective cohort study, patients undergoing (sub)total gastrectomy for gastric or gastroesophageal junction adenocarcinoma between 1996 and 2017 in a tertiary upper gastrointestinal center were included. The time was divided into a) before (1996-2006) (pre-CTx) and b) after (2006-2017) (CTx) the MAGIC trial. Data were comprehensively analyzed for demographics, tumor stage, perioperative treatment, surgery, histopathology, and survival rates (SR). RESULTS: 737 patients (32% female) underwent gastrectomy, 255 patients in the pre-CTx era and 482 patients in the CTx era. The median age was 65 years and the median follow-up was 27.5 months for surviving patients. Around 16.9% of patients received neoadjuvant treatment in the pre-CTx era versus 46.3% in the CTx era. The 3-year survival rate (3-YSR) was 46.4% in the pre-CTx and 60.9% in the CTx era (p < 0.001). For pretreated patients, 3-YSR was 39.0% (pre-CTx) versus 55.3% (CTx) (p = 0.168). Survival rate (SR) for locally advanced tumor stages (cT3/cT4) was higher when neoadjuvant therapy was administered (3-YSR: 56.7% vs 40.6%; p = 0.022). There were no significant differences according to sex (p = 0.357), age (p = 0.379), pT category (p = 0.817), pN stage (p = 0.074), cM stage (p = 0.112), Laurén classification (p = 0.158), and SRs (3-YSR: 60.3% vs 59.4%; p = 0.898) between the MAGIC and FLOT regimens. CONCLUSIONS: Survival rates have dramatically improved for gastric cancer patients during the last two decades. MAGIC and FLOT regimens showed similar results in the postsurgical follow-up.

New roles for B cell receptor associated kinases: when the B cell is not the target.

Targeting of B cell receptor associated kinases (BAKs), such as Bruton's tyrosine kinase (BTK) or phosphoinositol-3-kinase (PI3K) delta, by specific inhibitors has revolutionized the therapy of B lymphoid malignancies. BAKs are critical signaling transducers of BCR signaling and seem relevant in B cell lymphoma pathogenesis. The functional relevance of BTK for lymphoid malignancies is strongly supported by the observation that resistance to therapy in CLL patients treated with BTK inhibitors such as ibrutinib is often associated with mutations in genes coding for BTK or Phospholipase-C gamma (PLCÉ£). In some contrast, next generation sequencing data show that BAKs are mutated at very low frequency in treatment-naïve B cell lymphomas. Therefore, it remains debatable whether BAKs are essential drivers for lymphoma development. In addition, results obtained by targeted deletion of BAKs such as Lyn and Btk in murine CLL models suggest that BAKs may be essential to shape the dialogue between malignant B cells and the tumor microenvironment (TME). Since BAKs are expressed in multiple cell types, BAK inhibitors may disrupt the lymphoma supportive microenvironment. This concept also explains the typical response to BAK inhibitor treatment, characterized by a long-lasting increase of peripheral blood lymphoid cells, due to a redistribution from the lymphoid homing compartments. In addition, BAK inhibitors have shown some efficacy in solid tumors, probably through mediator cells in the TME. This review summarizes and validates the evidence for BAK inhibitors being part of a class of agents that modulate the (hematopoietic) microenvironment of cancers.