Category: Article scientifique

Biglycan expression in the melanoma microenvironment promotes invasiveness via increased tissue stiffness inducing integrin-β1 expression

Abstract
Novel targeted and immunotherapeutic approaches have revolutionized the treatment of metastatic melanoma. A better understanding of the melanoma-microenvironment, in particular the interaction of cells with extracellular matrix molecules, may help to further improve these new therapeutic strategies.We observed that the extracellular matrix molecule biglycan (Bgn) was expressed in certain human melanoma cells and primary fibroblasts when evaluated by microarray-based gene expression analysis. Bgn expression in the melanoma tissues correlated with low overall-survival and low progression-free-survival in patients. To understand the functional role of Bgn we used gene-targeted mice lacking functional Bgn. Here we observed that melanoma growth, metastasis-formation and tumor-related death were reduced in Bgn-/- mice compared to Bgn+/+ mice. In vitro invasion of melanoma cells into organotypic-matrices derived from Bgn-/- fibroblasts was reduced compared to melanoma invasion into Bgn-proficient matrices. Tissue stiffness as determined by atomic-force-microscopy was reduced in Bgn-/- matrices. Isolation of melanoma cells and fibroblasts from the stiffer Bgn+/+ matrices revealed an increase in integrin-β1 expression compared to the Bgn-/- fibroblast matrices. Overexpression of integrin-β1 in B16-melanoma cells abolished the survival benefit seen in Bgn-/- mice. Consistent with the studies performed in mice, the abundance of Bgn-expression in human melanoma samples positively correlated with the expression of integrin-β1, which is in agreement with results from the organotypic invasion-assay and the in vivo mouse studies.This study describes a novel role for Bgn-related tissue stiffness in the melanoma-microenvironment via regulation of integrin-β1 expression by melanoma cells in both mice and humans.

Keywords : biglycan; integrin-β1; melanoma; microenvironment; tissue stiffness

June 2017 / Oncotarget – written by Andrlová H, Mastroianni J, Madl J, Kern JS, Melchinger W, Dierbach H, Wernet F, Follo M, Technau-Hafsi K, Has C, Rao Mittapalli V, Idzko M, Herr R, Brummer T, Ungefroren H, Busch H, Boerries M, Narr A, Ihorst G, Vennin C, Schmitt-Graeff A, Minguet S, Timpson P, Duyster J, Meiss F, Römer W, Zeiser R

More details: https://www.ncbi.nlm.nih.gov/pubmed/28476030

MicroRNA-146a reduces MHC-II expression via targeting JAK/STAT signaling in dendritic cells after stem cell transplantation

Abstract
Acute Graft-versus-host disease (GVHD) is a major immunological complication after allogeneic hematopoietic cell transplantation and a better understanding of the molecular regulation of the disease could help to develop novel targeted therapies. Here we found that a G/C polymorphism within the human microRNA-146a (miR-146a) gene of transplant recipients, which causes reduced miR-146a levels, was strongly associated with the risk of developing severe acute GVHD (n=289). In mice, deficiency of miR-146a in the hematopoietic system or transfer of recipient-type miR-146a-/- dendritic cells (DCs) enhanced GVHD, while miR-146a mimic-transfected DCs ameliorated disease. Mechanistically, lack of miR-146a enhanced JAK2-STAT1 pathway activity, which led to higher expression of class II-transactivator (CIITA) and consecutively increased MHCII-levels on DCs. Inhibition of JAK1/2 or CIITA knockdown in DCs prevented miR-146a-/- DC-induced GVHD exacerbation. Consistent with our findings in mice, patients with the miR-146a polymorphism rs2910164 in hematopoietic cells displayed higher MHCII levels on monocytes, which could be targeted by JAK1/2 inhibition. Our findings indicate that the miR-146a polymorphism rs2910164 identifies patients at high risk for GVHD before allo-HCT. Functionally we show that miR-146a acts as a central regulator of recipient-type DC activation during GVHD by dampening the pro-inflammatory JAK-STAT/CIITA/MHCII axis, which provides a scientific rationale for early JAK1/2 inhibition in selected patients.Leukemia advance online publication, 26 May 2017; doi:10.1038/leu.2017.137.

May 2017 / Leukemia – written by Stickel N, Hanke K, Marschner D, Prinz G, Köhler M, Melchinger W, Pfeifer D, Schmitt-Graeff A, Brummer T, Heine A, Brossart P, Wolf D, von Bubnoff N, Finke J, Duyster J, Ferrara J, Salzer U, Zeiser R.

More details: https://www.ncbi.nlm.nih.gov/pubmed/28484267

Clinical Relevance of HLA Antibodies in Kidney Transplantation: Recent Data from the Heidelberg Transplant Center and the Collaborative Transplant Study

Abstract
Herein, we summarize our recent findings from the international Collaborative Transplant Study (CTS) and Heidelberg Transplant Center regarding the role of HLA antibodies in kidney transplantation and their application into the clinical routine. Based on the antibody findings from the CTS serum study, an algorithm was developed in 2006 for the transplantation of high-risk sensitized patients at the Heidelberg Transplant Center which includes seven different pre- and posttransplant measures. Using this algorithm, the number of transplantations could be increased in high-risk presensitized patients and the previously existing impact of antibodies on graft survival could greatly be diminished but not totally eliminated. More recent findings led to the hypothesis that T cell help from a preactivated immune system supports the harmful effects of pretransplant donor-specific HLA antibodies that otherwise disappear in many cases after transplantation without any consequence.

June 2017 / Journal of Immunology Research – Süsal C, Fichtner A, Tönshoff B, Mehrabi A, Zeier M, Morath C

More informations: https://www.ncbi.nlm.nih.gov/pubmed/28660215

An update on chemical pharmacotherapy options for the prevention of kidney transplant rejection with a focus on costimulation blockade

Abstract
The introduction of calcineurin inhibitors (CNI) has greatly improved graft survival in the past three decades. However, long-term graft survival is still limited due to chronic allograft injury and side-effects of immunosuppressive medication.
The present overview gives an update on pharmacotherapeutic strategies after kidney transplantation. The main focus is on CNI-sparing regimens using co-stimulatory blockade and on new substances on the horizone.

Keywords: Kidney transplantation, immunosuppressive regimens, calcineurin inhibitors, belatacept, mammalian target of rapamycin inhibitors, chronic antibody-mediated rejection

April 2017 / Expert Opinion on Pharmacotheraphy – written by Kälbe F, Schaier M, Schäffer S, Süsal C, Zeier M, Sommerer C et Morath C

More informations: http://www.tandfonline.com/doi/full/10.1080/14656566.2017.1323876

Natural Killer Group 2, Member D/NKG2D Ligands in Hematopoietic Cell Transplantation

Abstract
Natural killer group 2, member D (NKG2D) is an invariant activatory receptor present on subsets of natural killer and T lymphocytes. It stimulates the cytolytic effector response upon engagement of its various stress-induced ligands NKG2D ligands (NKG2DL). Malignant transformation and conditioning treatment prior to hematopoietic cell transplantation (HCT) are stress factors leading to the activation of the NKG2D/NKG2DL signaling in clinical settings. In the context of HCT, NKG2D-bearing cells can kill both tumor and healthy cells expressing NKG2DL. The NKG2D/NKG2DL engagement has therefore a key role in the regulation of one of the most salient issues in allogeneic HCT, i.e., maintaining a balance between graft-vs.-leukemia effect and graft-vs.-host disease. The present review summarizes the current state of our knowledge pertaining to the role of the NKG2D and NKG2DL in HCT.

March 2017 / Frontiers in Immunology – written by  Carapito R, Aouadi I, Ilias W and Bahram S

More details:  http://journal.frontiersin.org/article/10.3389/fimmu.2017.00368/full