A systems immunology approach identifies the collective impact of 5 miRs in Th2 inflammation.

Allergic asthma is a chronic inflammatory disease dominated by a CD4+ T helper 2 (Th2) cell signature. The immune response amplifies in self-enforcing loops, promoting Th2-driven cellular immunity and leaving the host unable to terminate inflammation. Posttranscriptional mechanisms, including microRNAs (miRs), are pivotal in maintaining immune homeostasis. Since an altered expression of various miRs has been associated with T cell-driven diseases, including asthma, we hypothesized that miRs control mechanisms ensuring Th2 stability and maintenance in the lung. We isolated murine CD4+ Th2 cells from allergic inflamed lungs and profiled gene and miR expression. Instead of focusing on the magnitude of miR differential expression, here we addressed the secondary consequences for the set of molecular interactions in the cell, the interactome. We developed the Impact of Differential Expression Across Layers, a network-based algorithm to prioritize disease-relevant miRs based on the central role of their targets in the molecular interactome. This method identified 5 Th2-related miRs (mir27b, mir206, mir106b, mir203, and mir23b) whose antagonization led to a sharp reduction of the Th2 phenotype. Overall, a systems biology tool was developed and validated, highlighting the role of miRs in Th2-driven immune response. This result offers potentially novel approaches for therapeutic interventions.

Rituximab as a therapeutic option for patients with advanced melanoma.

Treatment of metastatic melanoma remains challenging, despite a variety of new and promising immunotherapeutic and targeted approaches to therapy. New treatment options are still needed to improve long-term tumour control. We present a case series of seven patients with metastatic melanoma who were treated individually with the anti-CD20 antibody rituximab between July 2014 and July 2015. Two of the patients were treated in an adjuvant setting. All patients had already received a variety of treatments. During an induction phase, the administration of four cycles of weekly rituximab 375 mg/m2 body surface area was planned. After imaging, patients with stable disease continued therapy with rituximab 375 mg/m2 body surface area every 4 weeks up to a maximum of 24 weeks. Two patients experienced grade 2 infusion reactions during the first infusion. Otherwise, treatment was well tolerated and there were no grade 3 or 4 side effects. Staging after the induction phase showed stable disease in five patients, and two patients had progressive disease. Median progression-free survival was 6.3 months (95% CI 4.97-7.53), median overall survival was 14.7 months (95% CI 4.52-24.94), and one patient was still alive in December 2016. In conclusion, rituximab might be a therapeutic option for metastatic melanoma. However, further studies on rituximab among larger patient cohorts are warranted. Evaluation of therapy in an adjuvant setting or in combination with other systemic treatment might, therefore, be of particular interest.

Heading in the same direction: the skills-lab workshops Marburg-Goettingen - A field report.

HISTORY: After the initiation of skills-labs in Marburg and Goettingen the peer-teaching students of both institutions saw a need for communication and cooperation. The primary goal of these 'skills-lab workshops' was the exchange of already existing ideas for extracurricular peer-teaching, the development of new tutorials and long-term cooperation between the institutions. METHODS: In January of 2010 the 1(st) 'skills-lab workshop' Marburg-Goettingen was held at the 'Marburg's Interdisciplinary skills-lab' (Maris, since 10/2008). The 2(nd) workshop was held at the 'Student's trainings center of medical practice and simulation' (STÄPS, since 10/2009) in Goettingen in October of 2010. RESULTS AND CONCLUSION: Especially younger skills-labs can profit from an exchange with a more established Institution. Cooperations like these are the foundation for future exchange of ideas for new peer-teachings and the continuous improvement or a transfer of existing peer-teachings for skills-labs. We recommend bilateral exchanges like this to other and especially to new skills-labs.

Therapeutic T cells induce tumor-directed chemotaxis of innate immune cells through tumor-specific secretion of chemokines and stimulation of B16BL6 melanoma to secrete chemokines.

BACKGROUND: The mechanisms by which tumor-specific T cells induce regression of established metastases are not fully characterized. In using the poorly immunogenic B16BL6-D5 (D5) melanoma model we reported that T cell-mediated tumor regression can occur independently of perforin, IFN-gamma or the combination of both. Characterization of regressing pulmonary metastases identified macrophages as a major component of the cells infiltrating the tumor after adoptive transfer of effector T cells. This led us to hypothesize that macrophages played a central role in tumor regression following T-cell transfer. Here, we sought to determine the factors responsible for the infiltration of macrophages at the tumor site. METHODS: These studies used the poorly immunogenic D5 melanoma model. Tumor-specific effector T cells, generated from tumor vaccine-draining lymph nodes (TVDLN), were used for adoptive immunotherapy and in vitro analysis of chemokine expression. Cellular infiltrates into pulmonary metastases were determined by immunohistochemistry. Chemokine expression by the D5 melanoma following co-culture with T cells, IFN-gamma or TNF-alpha was determined by RT-PCR and ELISA. Functional activity of chemokines was confirmed using a macrophage migration assay. T cell activation of macrophages to release nitric oxide (NO) was determined using GRIES reagent. RESULTS: We observed that tumor-specific T cells with a type 1 cytokine profile also expressed message for and secreted RANTES, MIP-1alpha and MIP-1beta following stimulation with specific tumor. Unexpectedly, D5 melanoma cells cultured with IFN-gamma or TNF-alpha, two type 1 cytokines expressed by therapeutic T cells, secreted Keratinocyte Chemoattractant (KC), MCP-1, IP-10 and RANTES and expressed mRNA for MIG. The chemokines released by T cells and cytokine-stimulated tumor cells were functional and induced migration of the DJ2PM macrophage cell line. Additionally, tumor-specific stimulation of wt or perforin-deficient (PKO) effector T cells induced macrophages to secrete nitric oxide (NO), providing an additional effector mechanism for T cell-mediated tumor regression. CONCLUSION: These data suggest two possible sources for chemokine secretion that stimulates macrophage recruitment to the site of tumor metastases. Both appear to be initiated by T cell recognition of specific antigen, but one is dependent on the tumor cells to produce the chemokines that recruit macrophages.

Characterization of immune responses in gastric cancer patients: a possible impact of H. pylori to polarize a tumor-specific type 1 response?

Recently, we were able to show that Helicobacter pylori-positive gastric cancer (GC) patients have a significantly better survival after the complete resection of their tumor compared to H. pylori-negative GC patients. H. pylori is known to polarize an immune response towards a type 1 cytokine profile and tumor-specific type 1 cytokine responses are associated with protection from tumor challenge and T-cell-mediated tumor regression. Therefore, we hypothesized that the improved survival in H. pylori-positive patients may be secondary to the induction of a GC-specific type 1 T cell response. To characterize the anti-tumor immune response in GC patients we analyzed tumor-infiltrating lymphocytes (TIL) isolated from primary tumors. The CD3+ T cell population contained 50% CD4+ (range 0.4-81%) and 39% CD8+ cells (range 22-53%). The number of B cells (CD19+, P = 0.03) was significantly increased and the number of T cells (CD3+, P = 0.02) significantly decreased in intestinal compared to diffuse type of tumors. Four tumor cell lines were established from primary GCs and three from lymph node metastases. T cell cultures were established from isolated TIL from four H. pylori-positive and one H. pylori-negative GC patients and tested for tumor-specific cytokine secretion. Eight of ten T cell cultures derived from H. pylori-positive patients secreted both IFN-gamma and IL-5 after restimulation with autologous tumor cells. The only tumor-specific TIL line expressing a dominant IL-5 response was derived from an H. pylori-negative patient.

Adjuvant cisplatin plus methotrexate versus methotrexate, vinblastine, epirubicin, and cisplatin in locally advanced bladder cancer: results of a randomized, multicenter, phase III trial (AUO-AB 05/95).

PURPOSE: Radical cystectomy as standard treatment of muscle-invasive urothelial carcinoma of the urinary bladder cures less than 50% of patients with locally advanced bladder cancer. We compared two adjuvant combination chemotherapies in patients with stage pT3a-4a and/or pathologic node-positive transitional-cell carcinoma of the bladder after radical cystectomy. PATIENTS AND METHODS: A total of 327 patients were randomly assigned to either adjuvant systemic chemotherapy with three cycles of cisplatin 70 mg/qm(2) on day 1 and methotrexate 40 mg/qm(2) on days 8 and 15 of a 21-day cycle (CM) or three cycles of methotrexate 30 mg/qm(2) on days 1, 15, and 22, vinblastine 3 mg/qm(2) on days 2, 15, and 22, epirubicin 45 mg/qm(2) on day 2, and cisplatin 70 mg/qm(2) on day 2 of a 28-day cycle (M-VEC). RESULTS: The hazard ratio for progression-free survival as the primary end point was 1.13 (90% CI, 0.86 to 1.48) for 163 CM patients compared with 164 M-VEC patients whose right-hand limit remained below the upper bound compatible with the noninferiority hypothesis (alpha = .0403). The 5-year progression-free, tumor-specific, and overall survival rates (point estimates +/- SE) for CM versus M-VEC were 46.3% +/- 4.6% v 48.8% +/- 4.5%, 52.0% +/- 4.6% v 52.3% +/- 4.8%, and 46.1% +/- 4.3% v 45.1% +/- 4.6%, respectively. WHO grade 3 and 4 leukopenia occurred in 7.0% of patients treated with CM and 22.2% of patients treated with M-VEC (P < .0001). CONCLUSION: CM cannot be considered inferior to M-VEC with regard to progression-free survival of patients with locally advanced bladder cancer after radical cystectomy. Moreover, patients receiving adjuvant CM combination therapy experienced significantly less grade 3 and 4 leukopenia than patients treated with M-VEC.